JP2009530415A - Pharmaceutical composition - Google Patents

Abstract

The present invention provides forms and formulations of VX-950 and uses thereof. Specifically, the inventors have discovered improved forms and formulations of VX-950, eg, forms and formulations that have improved bioavailability compared to crystalline VX-950. These forms and formulations are useful for the treatment of HCV infection. It has also been discovered that the presence of two or more polymers (eg, multiple polymers) in a formulation containing VX-950 can help to provide improved properties, eg, can stabilize VX-950. . Accordingly, in one aspect, the disclosure features a preparation of amorphous VX-950, eg, a preparation of VX-950 that is substantially free of impurities and / or crystalline VX-950.

Description

(Cross-reference to related applications)
This application claims priority to US patent application Ser. No. 60 / 784,428, filed Mar. 20, 2006. The disclosure of said application is considered part of the present disclosure (and is incorporated by reference in the present disclosure).

(Technical field)
The present disclosure relates to pharmaceutical compositions.

(background)
Infections caused by hepatitis C virus (“HCV”) are a serious medical problem for humans. HCV is recognized as a causative factor for most cases of non-A and non-B hepatitis, and the human serum antibody positive rate is estimated to be 3% worldwide [Non-Patent Document 1]. It can be said that nearly 4 million people are infected in the United States alone [Non-patent document 2; Non-patent document 3].

  Upon initial exposure to HCV, only about 20% of infected individuals develop acute clinical hepatitis, and the rest of the people appear to resolve the infection naturally. However, in almost 70% of cases, this virus establishes a chronic infection that persists for decades [Non-Patent Document 4; Non-Patent Document 5]. This usually results in recurrent and gradually worsening hepatitis, which often leads to more serious disease states such as cirrhosis and hepatocellular carcinoma [Non-Patent Document 6; ]. It is estimated that 170 million people worldwide are infected with HCV. Over the next decade, the number of deaths attributed to hepatitis C is expected to increase significantly as a larger percentage of currently infected patients enter the third decade of their infection. Unfortunately, there is no widely effective treatment for the debilitating progression of chronic HCV.

  There are currently no perfectly satisfactory anti-HCV drugs or treatments. Interferon and PEGylated interferon are used for the treatment of HCV and may be administered in combination with ribavirin. Any treatment regimen containing interferon is known to have significant side effects, and thus there is a significant unmet medical need for safe and effective oral therapy for treating HCV . Moreover, the prospects for effective anti-HCV vaccines remain uncertain.

VX-950 is a competitive, reversible peptidomimetic HCV NS3 / 4A protease inhibitor with a steady state binding constant (ki ^* ) of 3 nM (and a Ki of 8 nM) [US Pat.

ＶＸ−９５０は、水に非常に不溶性である。
国際公開第０２／０１８３６９号パンフレット Ａ．Ａｌｂｅｒｔｉら，“Ｎａｔｕｒａｌ Ｈｉｓｔｏｒｙ ｏｆ Ｈｅｐａｔｉｔｉｓ Ｃ，”Ｊ．Ｈｅｐａｔｏｌｏｇｙ．３１．，（Ｓｕｐｐｌ．１），ｐｐ．１７−２４（１９９９） Ｍ．Ｊ．Ａｌｔｅｒら，“Ｔｈｅ Ｅｐｉｄｅｍｉｏｌｏｇｙ ｏｆ Ｖｉｒａｌ Ｈｅｐａｔｉｔｉｓ ｉｎ ｔｈｅ Ｕｎｉｔｅｄ Ｓｔａｔｅｓ，”Ｇａｓｔｒｏｅｎｔｅｒｏｌ．Ｃｌｉｎ．Ｎｏｒｔｈ Ａｍ．，２３，ｐｐ．４３７−４５５（１９９４） Ｍ．Ｊ．Ａｌｔｅｒ“Ｈｅｐａｔｉｔｉｓ Ｃ Ｖｉｒｕｓ Ｉｎｆｅｃｔｉｏｎ ｉｎ ｔｈｅ Ｕｎｉｔｅｄ Ｓｔａｔｅｓ，”Ｊ．Ｈｅｐａｔｏｌｏｇｙ．３１．，（Ｓｕｐｐｌ．１），ｐｐ．８８−９１（１９９９） Ｓ．Ｉｗａｒｓｏｎ，“Ｔｈｅ Ｎａｔｕｒａｌ Ｃｏｕｒｓｅ ｏｆ Ｃｈｒｏｎｉｃ Ｈｅｐａｔｉｔｉｓ，”ＦＥＭＳ Ｍｉｃｒｏｂｉｏｌｏｇｙ Ｒｅｖｉｅｗｓ．１４，ｐｐ．２０１−２０４（１９９４） Ｄ．Ｌａｖａｎｃｈｙ，“Ｇｌｏｂａｌ Ｓｕｒｖｅｉｌｌａｎｃｅ ａｎｄ Ｃｏｎｔｒｏｌ ｏｆ Ｈｅｐａｔｉｔｉｓ Ｃ，”Ｊ．Ｖｉｒａｌ Ｈｅｐａｔｉｔｉｓ，６，ｐｐ．３５−４７（１９９９） Ｍ．Ｃ．Ｋｅｗ，“Ｈｅｐａｔｉｔｉｓ Ｃ ａｎｄ Ｈｅｐａｔｏｃｅｌｌｕｌａｒ Ｃａｒｃｉｎｏｍａ”，ＦＥＭＳ Ｍｉｃｒｏｂｉｏｌｏｇｙ Ｒｅｖｉｅｗｓ．１４，ｐｐ．２１１−２２０（１９９４） Ｉ．Ｓａｉｔｏら，“Ｈｅｐａｔｉｔｉｓ Ｃ Ｖｉｒｕｓ Ｉｎｆｅｃｔｉｏｎ ｉｓ Ａｓｓｏｃｉａｔｅｄ ｗｉｔｈ ｔｈｅ Ｄｅｖｅｌｏｐｍｅｎｔ ｏｆ Ｈｅｐａｔｏｃｅｌｌｕｌａｒ Ｃａｒｃｉｎｏｍａ，”Ｐｒｏｃ．Ｎａｔｌ．Ａｃａｄ．Ｓｃｉ．ＵＳＡ．８７，ｐｐ．６５４７−６５４９（１９９０）

VX-950 is very insoluble in water.
International Publication No. 02/018369 Pamphlet A. Alberti et al., “Natural History of Hepatitis C,” J. et al. Hepatology. 31. , (Suppl. 1), pp. 17-24 (1999) M.M. J. et al. Alter et al., “The Epidemiology of Viral Hepatitis in the United States,” Gastroenterol. Clin. North Am. , 23, pp. 437-455 (1994) M.M. J. et al. Alter “Hepatitis C Virus Infection in the United States,” J. Hepatology. 31. , (Suppl. 1), pp. 88-91 (1999) S. Iwarson, “The Natural Course of Chronic Hepatitis,” FEMS Microbiology Reviews. 14, pp. 201-204 (1994) D. Lavanchy, "Global Survey and Control of Hepatitis C," J. Viral Hepatitis, 6, pp. 35-47 (1999) M.M. C. Kew, “Hepatitis C and Hepatoceral Carcinoma”, FEMS Microbiology Reviews. 14, pp. 211-220 (1994) I. Saito et al., “Hepatitis C Virus Infection is associated with the Development of Hepatocellular Carcinoma,” Proc. Natl. Acad. Sci. USA. 87, pp. 6547-6549 (1990)

(Summary)
The inventors have discovered improved forms and formulations of VX-950, eg, forms and formulations that have improved bioavailability compared to crystalline VX-950. These forms and formulations are useful for the treatment of HCV infection. It has also been discovered that the presence of two or more polymers (eg, multiple polymers) in a formulation containing VX-950 can help to provide improved properties, eg, can stabilize VX-950. .

  Accordingly, in one aspect, the disclosure features a preparation of amorphous VX-950, eg, a preparation of VX-950 that is substantially free of impurities and / or crystalline VX-950. For example, in one embodiment, the present disclosure increases the metastable solubility of VX-950 relative to the crystalline form, and thus provides an amorphous form of VX-950 that provides improved bioavailability. It is characterized by. The present disclosure includes numerous formulations containing amorphous forms of VX-950.

  In one aspect, the disclosure features a solid (eg, spray dried) dispersion comprising amorphous VX-950 and multiple polymers. The dispersion includes, for example, less than about 40% crystalline VX-950 (less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%). For example, the dispersion may be substantially free of crystalline VX-950.

  In a preferred embodiment, the solid dispersion exhibits a predetermined physical and / or chemical stability level. For example, the solid dispersion may be about 50%, about 60%, about 50% of amorphous VX-950 when stored at 25 ° C. in a closed watertight container, such as an amber glass vial or high density polyethylene (HDPE) container. Maintain 70%, about 80%, about 90%, about 95%, about 98%, or about 99%.

  In preferred embodiments, the solid dispersion, when administered to a fasted subject, is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 80% of the bioavailability when administered to a fed subject. It represents about 90%, at least about 95%, at least about 98%, or at least about 99%.

  In preferred embodiments, the solid dispersion, when administered to a fed subject, is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 80% of the bioavailability when administered to a fasted subject. It represents about 90%, at least about 95%, at least about 98%, or at least about 99%.

  In some embodiments, the solid dispersion also includes a surfactant (eg, sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof) or an inert pharmaceutically acceptable substance. In some embodiments, the surfactant is SLS. In some embodiments, the surfactant is vitamin E or a derivative thereof (eg, vitamin E TPGS).

  In some embodiments, the surfactant is between about 0.1% and about 10% (eg, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% ).

  In some embodiments, the multiple polymers include two polymers (eg, one or more water-soluble polymers or partially water-soluble polymers). In some embodiments, the plurality of polymers comprises a cellulose polymer.

  In some embodiments, the cellulose polymer is hydroxypropyl methylcellulose (HPMC; “hypromellose”) or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

  In some embodiments, the multiple polymers include two cellulose polymers, for example, one of the two cellulose polymers is hydroxypropyl methylcellulose (HPMC) and / or the two celluloses. One of the polymers is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the solid dispersion comprises HPMC and HPMCAS.

  In some embodiments, the solid dispersion further comprises a surfactant, a mixture of polymers, or an inert pharmaceutically acceptable substance. For example, the solid dispersion may comprise a mixture of polymers, the mixture of polymers being one or more water-soluble polymers or partially water-soluble polymers, eg, as described herein. May include a combination of polymers.

  In some embodiments, the dispersion comprises a surfactant or an inert pharmaceutically acceptable substance. For example, the surfactant is SLS or vitamin E or a derivative thereof (eg, vitamin E TPGS). In some embodiments, the surfactant is between about 0.1% and about 10% (eg, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% ). The amount of surfactant present in the solid dispersion depends on various factors, including, for example, the chemical nature of the surfactant. In some embodiments, the surfactant is about 0.1% to about 15%, such as about 0.1% to about 5%, preferably about 1% by weight in the solid dispersion. % Present.

  In some embodiments, the VX-950 has improved physical or chemical stability compared to amorphous VX-950 in the absence of a mixture of polymers. In some embodiments, the solid dispersion has a glass transition temperature higher than that of neat amorphous VX-950. In some embodiments, the VX-950 has a relaxation rate that is lower than that of neat amorphous VX-950.

  In some embodiments, the solid dispersion comprises a mixture of polymers including a cellulose polymer, such as an HPMC polymer or an HPMCAS polymer.

  In some embodiments, the mixture of polymers (eg, HPMC and HPMCAS) is about 10% to about 80%, eg, about 30% to about 75%, eg, , About 70%, about 50% or about 49.5% by weight.

  In some embodiments, VX-950 is about 10% to about 80%, such as about 30% to about 75%, such as about 70%, about 50%, in the solid dispersion. Present in an amount of weight percent or about 49.5 weight percent. In some embodiments, VX-950 is present in the solid dispersion in an amount greater than about 80% (eg, about 90%).

  In some embodiments, the solid dispersion comprises a surfactant, such as sodium lauryl sulfate or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  In some embodiments, substantially all of the VX-950 is present in the solid dispersion in an amorphous form.

  In some embodiments, the VX-950 is a mixture of L-isomer and D-isomer.

  In some embodiments, the VX-950 is a substantially pure L-isomer.

  In some embodiments, the solid dispersion is obtained by spray drying.

  In some embodiments, the multiple polymers have an amount or rate of crystallization of amorphous VX-950 of at least 10% (e.g., compared to a solid dispersion that is not present when the multiple polymers are present). , At least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%).

  In some embodiments, the multiple polymers are compared to a solid amorphous dispersion that is not present when the multiple polymers are present, or compared to neat VX-950 (eg, no polymer). The physical stability of amorphous VX-950 is at least 10% (eg, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least About 80%, or at least about 90%).

  In some embodiments, the large number of polymers can provide chemical or physical stability of the solid dispersion when stored (eg, at 2-8 ° C., such as 4 ° C., or at room temperature). At least 10% (eg, at least about 20%, at least about 30%, at least about 40%), as compared to a solid dispersion not present in the presence of multiple polymers of At least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%).

  In some embodiments, the VX-950 has improved physics (eg, in gastric fluid, SGF, intestinal fluid, SIF) compared to amorphous VX-950 in the absence of those multiple polymers. Has chemical or chemical stability. The large number of polymers can affect intestinal pH dissolution along the gastrointestinal tract.

  In some embodiments, the plurality of polymers (eg, HPMC and HPMCAS) is about 5% to about 80% (eg, about 10% to about 70%, about 20% to about 60% by weight). %, From about 30% to about 50% by weight).

  In a preferred embodiment, the solid dispersion comprises about 45% to about 85% VX-950, about 5% to about 25% HPMC polymer, such as HPMC 60SH50 or HPMC-E50, about 5% to about 30% HPMCAS. A polymer, such as HPMCAS-HG, and from about 0.1% to about 10% surfactant, such as SLS or vitamin E or a derivative thereof (eg, vitamin E TPGS), wherein the HPMC and HPMCAS are combined About 90%, about 95%, about 98%, about 99% or about 100% of the total polymer present.

  In a preferred embodiment, the solid dispersion exhibits a predetermined physical and / or chemical stability level. For example, the solid dispersion may be about 50%, about 60%, about 50% of amorphous VX-950 when stored at 25 ° C. in a closed watertight container, such as an amber glass vial or high density polyethylene (HDPE) container. Maintain 70%, about 80%, about 90%, about 95%, about 98% or about 99%.

  In some embodiments, the solid dispersion is between about 50% and about 60% (eg, about 55%) VX-950, between about 15% and about 25% (eg, about 19.6). %) HPMC polymer, such as HPMC60SH50, between about 20% and about 30% (eg, about 24.4%) HPMCAS polymer, such as HPMCAS-HG, and between about 0.1% and about 5% (eg, About 1%) of a surfactant, such as SLS.

  In some embodiments, the solid dispersion is between about 50% and about 60% (eg, about 55%) VX-950, between about 25% and about 35% (eg, about 29.3). %) HPMC polymer, such as HPMC60SH50, between about 10% and about 20% (eg, about 14.7%) HPMCAS polymer, such as HPMCAS-HG, and between about 0.1% and about 5% (eg, , About 1%) of a surfactant, such as SLS.

In some embodiments, the solid dispersion is between about 55% and about 65% (eg, about 60%) VX-950, between about 10% and about 20% (eg, about 14.6). %) HPMC polymer, such as HPMC60SH50, between about 20% and about 30% (eg, about 24.4%) HPMCAS polymer, such as HPMCAS-HG, and between about 0.1% and about 5% (eg, In some embodiments, the solid dispersion comprises between about 60% and about 70% (eg, about 65%) of VX-950, about 12%, % And about 22% (eg, about 17%) HPMC polymers, such as HPMC60SH50, between about 12% and about 22% (eg, about 17%) HPMCAS polymers, such as HPMCAS-HG, and about 0.1%. 1% And about 5% (eg, about 1%) of a surfactant, such as SLS.

  In some embodiments, the solid dispersion is between about 65% and about 75% (eg, about 70%) VX-950, between about 15% and about 25% (eg, about 19.6). %) HPMC polymer, such as HPMC60SH50, between about 5% and about 15% (eg, about 9.7%) HPMCAS polymer, such as HPMCAS-HG, and between about 0.1% and about 5% (eg, About 1%) of a surfactant, such as SLS.

  In some embodiments, the first polymer is present in an amount between about 1% and about 99%, and the second polymer is present in an amount between about 1% and 99%, where The amount of the first and second polymers totals 100% of the total polymer present in the solid dispersion.

  In some embodiments, the first polymer is present in an amount between about 28% and about 38% (eg, about 33%) of the total polymer amount, and the second polymer is about 62%. % And about 72% (eg, about 67%).

  In some embodiments, the first polymer is present in an amount between about 47% and about 57% (eg, about 52%) of the total polymer amount, and the second polymer is about 43%. % And about 53% (eg, about 48%).

  In some embodiments, the first polymer is present in an amount between about 58% and about 68% (eg, about 63%) of the total polymer amount, and the second polymer is about 32%. % And about 42% (eg, about 37%).

  In some embodiments, the first polymer is present in an amount between about 45% and about 55% (eg, about 50%) of the total polymer amount, and the second polymer is about 45%. % And about 55% (eg, about 50%).

  In some embodiments, the first polymer is HPMCAS. In some embodiments, the second polymer is HPMC. In some embodiments, the first polymer is HPMC and the second polymer is HPMCAS.

  In some embodiments, the present disclosure provides a solid dispersion of VX-950, such as an amorphous solid dispersion. For example, an amorphous solid dispersion comprising VX-950, a mixture of polymers, and optionally one or more solubility enhancing surfactants is provided. The dispersion can improve the water solubility and bioavailability of VX-950 when the solid dispersion is orally administered to a mammal (eg, rat, dog or human). In certain embodiments, at least a portion of VX-950 in the solid dispersion (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%) is in an amorphous state. In a preferred embodiment, the solid dispersion is essentially or substantially free of crystalline VX-950.

  In certain solid dispersions, VX-950 (eg, amorphous VX-950) is about 99% or less, eg, about 98% or less, about 95% or less, about 90% of the total weight of the solid dispersion. % Or less, about 85% or less, about 80% or less, about 70% or less, preferably about 70% or less, about 65% or less, about 60% or less, about 55% or less, and more preferably about 50% or less Present in the amount of. In other embodiments, VX-950 is at least about 1% of the solid dispersion, such as at least about 2%, at least about 3%, at least about 4%, preferably at least about 5%, at least about 6%. , At least about 7%, at least about 8%, at least about 9%, more preferably at least about 10%, and even more preferably at least about 50%. As shown in the examples herein, solid dispersions in which VX-950 is present in an amount of about 50% by weight (and more particularly about 49.5%) are encompassed by the present disclosure.

  In some embodiments, when VX-950 is in a solid dispersion, at least about 60% by weight of VX-950, such as at least about 65%, at least about 70%, at least about 75%, Preferably, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight are in amorphous form. Also included are dispersions in which all or substantially all VX-950 is amorphous.

  In some embodiments, the dispersion comprising VX-950 comprises a mixture of L- and D-isomers (eg, 1: 1) of VX-950, or VX-950 is substantially It can be any pure isomer. For example, a mixture of about 60:40 L: D (+/− 5%) is included. In certain embodiments, the VX-950 is present in an L-isomer amount greater than about 95%, about 98%, or about 98%.

Amorphous solid dispersions generally exhibit a glass transition temperature at which the dispersion transitions from a glassy solid to a rubbery composition. In general, the higher the glass transition temperature, the higher the physical stability of the dispersion. The presence of a glass transition temperature generally indicates that at least a majority of the composition (eg, dispersion) is in an amorphous state. The glass transition temperature (T _g ) of solid dispersions suitable for pharmaceutical use is generally at least about 50 ° C. In some embodiments, higher temperatures are preferred. Accordingly, in some embodiments, a solid dispersion of the present disclosure is at least about 100 ° C. (eg, at least about 100 ° C., at least about 105 ° C., at least about 110 ° C., at least about 115 ° C., at least about 120 ° C., at least About 125 ° C, at least about 130 ° C, at least about 135 ° C, at least about 140 ° C, at least about 150 ° C, at least about 160 ° C, at least about 170 ° C, at least about 175 ° C, at least about 180 ° C, or at least about 190 ° C) Having a T _g of In some preferred embodiments, the T _g is about 200 ° C. or less. Unless stated otherwise, the glass transition temperatures described herein are measured under dry conditions.

  In another aspect, the disclosure features a pharmaceutical composition of amorphous VX-950 and a number of polymers (eg, as described herein).

  In a preferred embodiment, the solid dispersion exhibits a predetermined physical and / or chemical stability level. For example, the solid dispersion may be about 50%, about 60%, about 50% of amorphous VX-950 when stored at 25 ° C. in a closed watertight container, such as an amber glass vial or high density polyethylene (HDPE) container. Maintain 70%, about 80%, about 90%, about 95%, about 98% or about 99%.

  In some embodiments, the amorphous VX-950 is substantially free of crystalline VX-950.

  In some embodiments, the pharmaceutical composition comprises amorphous VX-950 and a number of polymers as a solid dispersion and a surfactant, an inert pharmaceutically acceptable substance or a pharmaceutically acceptable carrier. One or more of the above.

  In some embodiments, the multiple polymers comprise one or more water-soluble polymers or partially water-soluble polymers.

  In some embodiments, the VX-950 has improved physical or chemical stability relative to crystalline VX-950.

  In some embodiments, the multiple polymers are amorphous VX-950 crystals compared to a pharmaceutical composition where the multiple polymers are not present, or compared to neat VX-950. At least about 20%, for example at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) decrease.

  In some embodiments, the multiple polymers are chemically or physically associated with the pharmaceutical composition as compared to a pharmaceutical composition where the multiple polymers are not present, or compared to neat VX-950. At least 10% (eg, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) ) Increase.

  In some embodiments, the VX-950 has improved physical or chemical stability compared to amorphous VX-950 that is not in the presence of multiple polymers thereof.

  In some embodiments, the plurality of polymers comprises HPMC or HPMCAS.

In some embodiments, the disclosure features a pharmaceutical composition comprising:
An amorphous solid dispersion of VX-950, wherein said VX-950 comprises about 25-85% (w / w) of the pharmaceutical composition;
A number of polymers (in which case the number comprises two cellulose polymers, and the number of polymers comprises about 15-75% (weight / weight) of the pharmaceutical composition), and a surfactant ( In this case, the surfactant constitutes about 0.5-2% (weight / weight) of the pharmaceutical composition).

  In some embodiments, the cellulose polymer is HPMC or HPMCAS.

  In some embodiments, the surfactant is sodium lauryl sulfate or vitamin E TPGS.

  In some embodiments, the VX-950 comprises about 55% to about 70% (w / w) of the pharmaceutical composition, and the surfactant is sodium lauryl sulfate or vitamin E TPGS; And about 1% (weight / weight) of the pharmaceutical composition, and the multiple polymers comprise HPMC and HPMCAS, comprising about 44% to about 29% (weight / weight) of the pharmaceutical composition As a result, the total amount is 100% (weight / weight) of the composition.

  In some embodiments, the VX-950 comprises about 55% (w / w) of the pharmaceutical composition and the multiple polymers comprise about 44% (w / w) of the pharmaceutical composition. And the surfactant is sodium lauryl sulfate or vitamin E TPGS and constitutes about 1% (w / w) of the pharmaceutical composition. In some embodiments, the multiple polymers comprise about 55.5% (w / w) HPMCAS and about 44.5% (w / w) HPMC.

  In some embodiments, the VX-950 comprises about 55% (w / w) of the pharmaceutical composition and the multiple polymers comprise about 44% (w / w) of the pharmaceutical composition. And the surfactant is sodium lauryl sulfate or vitamin E TPGS and constitutes about 1% (w / w) of the pharmaceutical composition. In some embodiments, the multiple polymers comprise about 33% (w / w) HPMCAS and about 67% (w / w) HPMC.

  In some embodiments, the VX-950 comprises about 60% (w / w) of the pharmaceutical composition and the multiple polymers comprise about 39% (w / w) of the pharmaceutical composition. And the surfactant is sodium lauryl sulfate or vitamin E TPGS and constitutes about 1% (w / w) of the pharmaceutical composition. In some embodiments, the multiple polymers comprise about 63% (w / w) HPMCAS and about 36% (w / w) HPMC.

  In some embodiments, the VX-950 comprises about 65% (w / w) of the pharmaceutical composition and the multiple polymers comprise about 34% (w / w) of the pharmaceutical composition. And the surfactant is sodium lauryl sulfate or vitamin E TPGS and constitutes about 1% (w / w) of the pharmaceutical composition. In some embodiments, the multiple polymers comprise about 50% (w / w) HPMCAS and about 50% (w / w) HPMC.

  In some embodiments, the VX-950 comprises about 70% (w / w) of the pharmaceutical composition and the multiple polymers comprise about 29% (w / w) of the pharmaceutical composition. And the surfactant is sodium lauryl sulfate or vitamin E TPGS and constitutes about 1% (w / w) of the pharmaceutical composition. In some embodiments, the multiple polymers comprise about 33% (w / w) HPMCAS and about 67% (w / w) HPMC.

  In another aspect, the disclosure provides amorphous VX-950 as a solid dispersion and a surfactant, polymer, inert pharmaceutically acceptable substance or pharmaceutically acceptable carrier (eg, the present And a pharmaceutical composition comprising one or more of those as described in the specification.

  In a preferred embodiment, the solid dispersion exhibits a predetermined physical and / or chemical stability level. For example, the solid dispersion may be about 50%, about 60%, about 50% of amorphous VX-950 when stored at 25 ° C. in a closed watertight container, such as an amber glass vial or high density polyethylene (HDPE) container. Maintain 70%, about 80%, about 90%, about 95%, about 98%, or about 99%.

  In preferred embodiments, the solid dispersion, when administered to a fasted subject, is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 80% of the bioavailability when administered to a fed subject. It represents about 90%, at least about 95%, at least about 98%, or at least about 99%.

  In preferred embodiments, the solid dispersion, when administered to a fed subject, is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 80% of the bioavailability when administered to a fasted subject. It represents about 90%, at least about 95%, at least about 98%, or at least about 99%.

  In some embodiments, the composition comprises a mixture of polymers, and the polymer mixture comprises one or more water-soluble polymers or partially water-soluble polymers.

  In some embodiments, the VX-950 has improved physical or chemical stability relative to crystalline VX-950. In some embodiments, the solid dispersion has a glass transition temperature higher than that of neat amorphous VX-950. In some embodiments, the VX-950 has a relaxation rate that is lower than that of neat amorphous VX-950.

  In some embodiments, the mixture of polymers comprises a cellulosic polymer, such as HPMC or HPMCAS.

  In some embodiments, the mixture of polymers comprises HPMC and / or HPMCAS.

  In some embodiments, the pharmaceutical composition also includes a surfactant, either in solution or as a component of VX-950 particles, or both. The surfactant can be, for example, SLS or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  Methods for preparing the forms, dispersions, compositions or formulations described herein.

  Accordingly, a method for preparing an amorphous form of VX-950 including spray drying is described. One embodiment combines VX-950 with a suitable solvent to make a mixture, and then spray-dried the mixture to obtain amorphous form of VX-950. Provide a preparation process. The mixture may be either a solution or a suspension.

  In another aspect, the disclosure features a solid dispersion prepared according to the processes described herein.

This disclosure
a) making a solution of a mixture of VX-950 and a polymer (eg, a crystallization inhibiting or stabilizing polymer) and a solvent;
b) for preparing a solid dispersion of VX-950 comprising rapidly removing the solvent from the solution to produce a solid amorphous dispersion comprising VX-950 and a crystallization inhibiting polymer mixture. A process is also provided. In certain embodiments, the solvent is removed by spray drying.

  As will be appreciated, spray drying can and is often done in the presence of an inert gas. In certain embodiments, processes involving spray drying can be performed in the presence of a supercritical fluid comprising carbon dioxide or a mixture of carbon dioxide.

Accordingly, in another embodiment, the present disclosure provides:
a) Make a mixture of VX-950 and a polymer (eg, one or more of the following: a supporting polymer, a crystallization inhibiting polymer, or a stabilizing polymer) and a solvent (or mixture of solvents). And b) providing a process for preparing a solid dispersion of VX-950 comprising spray drying the mixture to produce a solid dispersion comprising VX-950.

  Post-drying and / or polishing of the wet spray-dried dispersion below a given specification for ICH or residual solvent may optionally be performed.

  These processes can be used to prepare the compositions of the present disclosure. The amounts and characteristics of the components used in the process will be as described herein.

  In some embodiments, the process for preparing a solid dispersion containing amorphous form of VX-950 and a number of polymers comprises spray drying VX-950 and the number of polymers to produce VX-950. Producing a solid dispersion of

  In some embodiments, the process comprises combining VX-950 with a number of polymers and a suitable solvent to form a mixture, and then spray drying the mixture to produce a solid dispersion of VX-950. Including.

In some embodiments, the process comprises
a) making a mixture comprising VX-950 and a number of polymers and solvent; and b) spray drying the mixture to produce a solid dispersion comprising VX-950.

  In some embodiments, the multiple polymers include HPMC and / or HPMCAS.

  In some embodiments, the multiple polymers are present in the solid dispersion in an amount from about 20 weight percent to about 60 weight percent.

  In some embodiments, the mixture of polymers is present in the solid dispersion in an amount of about 30% to about 70% by weight.

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  In some embodiments, the solvent comprises methylene chloride. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises a mixture of methylene chloride and acetone. For example, the solvent may comprise about 0% to about 30% acetone and about 70% to about 100% methylene chloride, or the solvent comprises about 0% to about 40% acetone and about 60% To about 100% methylene chloride. Other exemplary ratios of methylene chloride to acetone include 80:20, 75:25, 70:30, and 60:40.

  In some embodiments, the mixture further comprises a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E TPSG.

  In some embodiments, the solvent comprises methylene chloride.

  In some embodiments, the solvent comprises acetone.

  In some embodiments, the solvent comprises about 0% to about 30% acetone and about 70% to about 100% methylene chloride.

  In some embodiments, the solvent comprises about 0% to about 40% acetone and about 60% to about 100% methylene chloride.

  In some embodiments, a solid dispersion prepared according to the process described herein.

  In some aspects, the disclosure features a method of treating an HCV infection in a mammal comprising administering a solid dispersion described herein.

  In one aspect, the disclosure features a pharmaceutical pack or kit comprising a solid dispersion of VX-950 disclosed herein.

  In one aspect, the disclosure features an oral formulation (eg, a tablet) comprising a solid dispersion of VX-950 disclosed herein.

  In another aspect, the disclosure features a method of treating HCV infection in a mammal. In some embodiments, the method comprises administering amorphous VX-950, wherein amorphous VX-950 is as defined herein. In another embodiment, the method comprises administering a solid dispersion described herein.

  In another embodiment, the method comprises: an immunomodulator; an antiviral agent; another inhibitor of HCV NS3 / 4A protease; another inhibitor of IMPDH; inhibition of a target other than NS3 / 4A protease in the HCV life cycle Administering an additional agent selected from an agent; a ribosome internal entry inhibitor, a broad spectrum virus inhibitor; a cytochrome P-450 inhibitor; or a combination thereof.

  In another aspect, the disclosure features a pharmaceutical pack or kit comprising a VX-950 composition or amorphous VX-950 as described herein.

  Amorphous forms of drugs can exhibit different properties than crystalline forms (see US Pat. No. 6,627,760). Embodiments of the present disclosure include amorphous VX-950 that is at a thermodynamically higher energy level than its corresponding crystalline form. Thus, it is energetically more active and therefore often exhibits higher metastable solubility, faster dissolution behavior, and less stable physical properties. The first two properties act to improve the water solubility and bioavailability of the drug, while the last property is due to recrystallization of the drug during storage from its amorphous state, or Administration to humans or animals can be detrimental to this goal as it results in a physically less stable composition that may change bioavailability.

  In order to improve the stability of amorphous solids (generally less stable than the crystalline form), a mixture of polymers can be used to make an amorphous solid dispersion system with the drug.

  The production of an amorphous solid dispersion containing VX-950 presents several challenges. First, VX-950 does not dissolve to a significant amount in water or most other conventional organic solvents (including acetone, ethyl acetate and acetonitrile). The water solubility of VX-950 at room temperature is virtually undetectable by HPLC and its water solubility is independent of pH. Second, VX-950 shows chemical reactivity with some alcohols, such as MeOH, EtOH and iPrOH, which makes them unsuitable solvents. Third, the melting point of VX-950 is about 240 ° C., which makes hot melt technology somewhat impractical. This is because of the possibility of decomposition of VX-950 at high temperatures. Thus, a suitable solvent or solvent mixture is very important for optimizing the processing and production of solid dispersions.

  The amorphous solid dispersions of the present disclosure can significantly improve the oral bioavailability of VX-950. In the presence of a suitable surfactant or surfactant mixture (eg, SLS or vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS)), its bioavailability can be further improved.

  The amorphous solid dispersions of the present disclosure can provide improved bioavailability of VX-950 when administered orally compared to administration of crystalline VX-950. In some embodiments, these solid dispersions are in a solid state that can be stored and administered conventionally. The production of the solid dispersion can be successfully implemented and scaled by selecting an organic solvent or solvent mixture (eg methyl chloride, acetone, etc.) or a supercritical fluid (eg containing carbon dioxide). it can. In some embodiments, the solid dispersion can have improved chemical and physical stability. For example, in some cases, the solid dispersion can be chemically and / or physically stable for at least two years at conventional storage conditions (room temperature).

  During spray drying of a drug or other therapeutic agent (eg, a solid dispersion of the drug or therapeutic agent), the inventors have produced various solvents, including, for example, non-volatile or high boiling solvents. It has been discovered that the properties of a product (eg, a solid dispersion such as an amorphous solid dispersion of the drug or therapeutic agent) can be improved. In some cases, the inclusion of a non-volatile or high boiling solvent as a component of the solvent mixture in the spray drying process can increase the amount of time required to solidify and / or dry the resulting particles, thereby In some cases, yielding improved particles, for example particles that are larger and / or denser and / or flowable than the same particles obtained using a solvent system without non-volatile or high boiling solvents. Can be made.

  In one embodiment, the method comprises a method of spray drying a drug or other therapeutic agent, the method comprising a suitable solvent or mixture of solvents (in this case at least one solvent) to make a mixture of drug and solvent. Make a mixture of drugs in a non-volatile or high boiling solvent); and then spray dry the mixture to obtain an amorphous drug product. The mixture may be either a solution or a suspension.

  In some embodiments, the drug is a small molecule drug, such as a drug having a molecular weight of less than about 1000 daltons, such as less than about 750 daltons or less than 500 daltons.

  In some embodiments, the drug is a low solubility drug.

  The drug can be selected from one of the following categories: analgesics, anti-inflammatory drugs, anthelmintic drugs, antiarrhythmic drugs, antibacterial drugs, antiviral drugs, anticoagulants, antidepressants, antidiabetics Drugs, antiepileptic drugs, antifungal drugs, antigout drugs, antihypertensive drugs, antimalarial drugs, antimigraine drugs, antimuscarinic agonists, antineoplastic drugs, erectile dysfunction drugs, immunosuppressants, antiprotozoal , Antithyroid, anxiolytic, sedative, hypnotic, neuroleptic, beta-blocker, cardiotonic, corticosteroid, diuretic, antiparkinsonian, gastrointestinal, histamine receptor antagonist, keratolytic , Lipid regulators, antianginal drugs, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutrients, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, Anti-osteoporosis drugs, anti-obesity drugs, cognitive enhancement , Anti-urinary incontinence agents, edible oils, anti-benign prostatic hyperplasia agents, essential fatty acids or non-essential fatty acids.

  In some preferred embodiments, the drug is an antiviral agent, eg, an antiviral agent used to treat hepatitis C (HepC), eg, a HepC protease inhibitor. In some most preferred embodiments, the drug is VX-950:

一部の実施形態において、前記溶媒は、少なくとも１つの不揮発性溶媒を含む溶媒成分の組み合わせである。例えば、前記溶媒は、揮発性溶媒と不揮発性溶媒の両方を含む成分の組み合わせである。

In some embodiments, the solvent is a combination of solvent components comprising at least one non-volatile solvent. For example, the solvent is a combination of components including both volatile and non-volatile solvents.

  Examples of suitable volatile solvents include those that dissolve or suspend the drug, alone or in combination with another co-solvent. In some preferred examples, the solvent or combination of solvents completely dissolves the drug.

  Examples of volatile solvents include methylene chloride, acetone, chloroform and THF. Examples of non-volatile solvents include organic acids such as glacial acetic acid, DMSO, DMF or water.

  In some embodiments, the non-volatile solvent is a component of a solvent system. For example, the non-volatile solvent may comprise from about 1% to about 20% (eg, from about 3% to about 15%, from about 4% to about 12%, or about 5% by weight as a component in the solvent. % To about 10% by weight).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination such as methylene chloride and acetone and a non-volatile solvent such as glacial acetic acid. For example, the solvent system may comprise about 40% to about 80% methylene chloride, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (eg, about 50% to about 70% methylene chloride, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

  In some embodiments, the solvent system comprises glacial acetic acid.

  In some embodiments, the solvent system comprises a combination of glacial acetic acid and at least one volatile solvent, such as acetone and / or methylene chloride (eg, a mixture of methylene chloride and acetone).

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or combination of solvents such as methylene chloride and acetone and a non-volatile solvent such as water. For example, the solvent system can include from about 40% to about 80% methylene chloride, from about 20% to about 35% acetone, and from about 0.1% to about 15% water (eg, from about 50% to about 70% methylene chloride, About 25% to about 30% acetone, and about 1% to about 5% water).

  In some embodiments, the solvent system includes water.

  In some embodiments, the solvent system comprises a combination of water and at least one volatile solvent, such as acetone and / or methylene chloride (eg, a mixture of methylene chloride and acetone).

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  In another embodiment, the spray-drying method is suitable for making a mixture of drug, polymer (s) and solvent, wherein the at least one solvent is a non-volatile or high boiling solvent. A mixture of the drug and one or more polymers; and then spray-drying the mixture to obtain a solid dispersion drug product. Including the formation of a solid dispersion. The mixture may be either a solution or a suspension. In a preferred embodiment, the solid dispersion product is an amorphous solid dispersion. For example, an amorphous solid dispersion that is substantially free of crystalline formulations.

  Examples of polymers for the solid dispersion include one or more water soluble polymers or partially water soluble polymers. Water-soluble or partially water-soluble polymers include cellulose derivatives (eg, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol ( PVA); acrylates such as polymethacrylates (e.g. Eudragit <(R)> E); cyclodextrins (e.g. [beta] -cyclodextrin), and these including, e.g. PVP-VA (polyvinylpyrrolidone-vinyl acetate) Copolymers and derivatives include, but are not limited to.

  In some preferred embodiments, the polymer is hydroxypropyl methylcellulose (HPMC), such as HMPC60SH50, HPMC E50, or HPMC E15.

  In some embodiments, the polymer is a pH dependent enteric polymer. Examples of such pH-dependent enteric polymers include cellulose derivatives (eg, cellulose acetate phthalate (CAP)), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or salts thereof. (For example, sodium salts such as (CMC-Na)), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP) ), Or polymethacrylate (e.g., Eudragit <(R)> S), But it is not limited to these.

  In some preferred embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS), such as HMPC AS-HG.

  In another embodiment, the polymer (s) is an insoluble cross-linked polymer, such as polyvinylpyrrolidone (eg, crospovidone).

  In another embodiment, the polymer (s) is polyvinyl pyrrolidone (PVP).

  In some embodiments, the polymer is a mixture of two or more polymers (eg, a combination of two cellulosic polymers such as HPMC and HPMCAS).

  In some embodiments, the polymer (s) is present in the solid dispersion in an amount from about 30% to about 70% by weight.

  In some embodiments, the drug is a small molecule drug, such as a drug having a molecular weight of less than about 1000 daltons, such as less than about 750 daltons or less than 500 daltons.

  In some embodiments, the drug is a low solubility drug.

  The drug can be selected from one of the following categories: analgesics, anti-inflammatory drugs, anthelmintic drugs, antiarrhythmic drugs, antibacterial drugs, antiviral drugs, anticoagulants, antidepressants, antidiabetics Drugs, antiepileptic drugs, antifungal drugs, antigout drugs, antihypertensive drugs, antimalarial drugs, antimigraine drugs, antimuscarinic agonists, antineoplastic drugs, erectile dysfunction drugs, immunosuppressants, antiprotozoal , Antithyroid, anxiolytic, sedative, hypnotic, neuroleptic, beta-blocker, cardiotonic, corticosteroid, diuretic, antiparkinsonian, gastrointestinal, histamine receptor antagonist, keratolytic , Lipid regulators, antianginal drugs, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutrients, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, Anti-osteoporosis drugs, anti-obesity drugs, cognitive enhancement , Anti-urinary incontinence agents, edible oils, anti-benign prostatic hyperplasia agents, essential fatty acids or non-essential fatty acids.

  In some preferred embodiments, the drug is an antiviral agent, eg, an antiviral agent used to treat HepC, eg, a HepC protease inhibitor. In some most preferred embodiments, the drug is VX-950:

一部の実施形態において、前記溶媒は、少なくとも１つの不揮発性溶媒を含む溶媒成分の組み合わせである。例えば、前記溶媒は、揮発性溶媒と不揮発性溶媒の両方を含む成分の組み合わせである。

In some embodiments, the solvent is a combination of solvent components comprising at least one non-volatile solvent. For example, the solvent is a combination of components including both volatile and non-volatile solvents.

  Examples of suitable volatile solvents include those that dissolve or suspend the drug, alone or in combination with another co-solvent. In some preferred examples, the solvent or combination of solvents completely dissolves the drug.

  Examples of volatile solvents include methylene chloride, acetone, chloroform and THF. Examples of non-volatile solvents include organic acids such as glacial acetic acid, DMSO, DMF or water.

  In some embodiments, the non-volatile solvent is a component of a solvent system. For example, the non-volatile solvent may comprise from about 1% to about 20% (eg, from about 3% to about 15%, from about 4% to about 12%, or about 5% by weight as a component in the solvent. % To about 10% by weight).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination such as methylene chloride and acetone and a non-volatile solvent such as glacial acetic acid. For example, the solvent system may comprise about 40% to about 80% methylene chloride, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (eg, about 50% to about 70% methylene chloride, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or combination of solvents such as methylene chloride and acetone and a non-volatile solvent such as water. For example, the solvent system can include from about 40% to about 80% methylene chloride, from about 20% to about 35% acetone, and from about 0.1% to about 15% water (eg, from about 50% to about 70% methylene chloride, About 25% to about 30% acetone, and about 1% to about 5% water).

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

In another aspect, the process comprises
a) making or producing a mixture of a low water-soluble drug, at least one polymer and a solvent system comprising at least one non-volatile solvent; and b) spray-drying the mixture to contain the low water-soluble drug Making a solid dispersion to obtain a solid dispersion of the drug.

  In some embodiments, the drug is a small molecule drug, such as a drug having a molecular weight of less than about 1000 daltons, such as less than about 750 daltons or less than 500 daltons.

  The drug can be selected from one of the following categories: analgesics, anti-inflammatory drugs, anthelmintic drugs, antiarrhythmic drugs, antibacterial drugs, antiviral drugs, anticoagulants, antidepressants, antidiabetics Drugs, antiepileptic drugs, antifungal drugs, antigout drugs, antihypertensive drugs, antimalarial drugs, antimigraine drugs, antimuscarinic agonists, antineoplastic drugs, erectile dysfunction drugs, immunosuppressants, antiprotozoal , Antithyroid, anxiolytic, sedative, hypnotic, neuroleptic, beta-blocker, cardiotonic, corticosteroid, diuretic, antiparkinsonian, gastrointestinal, histamine receptor antagonist, keratolytic , Lipid regulators, antianginal drugs, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutrients, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, Anti-osteoporosis drugs, anti-obesity drugs, cognitive enhancement , Anti-urinary incontinence agents, edible oils, anti-benign prostatic hyperplasia agents, essential fatty acids or non-essential fatty acids.

  In some preferred embodiments, the drug is an antiviral agent, eg, an antiviral agent used to treat HepC, eg, a HepC protease inhibitor. In some most preferred embodiments, the drug is VX-950:

一部の実施形態において、前記溶媒は、少なくとも１つの不揮発性溶媒を含む溶媒の組み合わせである。例えば、前記溶媒は、揮発性溶媒と不揮発性溶媒の両方を含む成分の組み合わせである。

In some embodiments, the solvent is a combination of solvents comprising at least one non-volatile solvent. For example, the solvent is a combination of components including both volatile and non-volatile solvents.

  Examples of suitable volatile solvents include those that dissolve or suspend the drug, alone or in combination with another co-solvent. In some preferred examples, the solvent or combination of solvents completely dissolves the drug.

  Examples of volatile solvents include methylene chloride, acetone, chloroform and THF.

  Examples of non-volatile solvents include organic acids such as glacial acetic acid, DMSO, DMF or water.

  In some embodiments, the non-volatile solvent is a component of a solvent system. For example, the non-volatile solvent may comprise from about 1% to about 20% (eg, from about 3% to about 15%, from about 4% to about 12%, or about 5% by weight as a component in the solvent. % To about 10% by weight).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination such as methylene chloride and acetone and a non-volatile solvent such as glacial acetic acid. For example, the solvent system may comprise about 40% to about 80% methylene chloride, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (eg, about 50% to about 70% methylene chloride, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or combination of solvents such as methylene chloride and acetone and a non-volatile solvent such as water. For example, the solvent system can include from about 40% to about 80% methylene chloride, from about 20% to about 35% acetone, and from about 0.1% to about 15% water (eg, from about 50% to about 70% methylene chloride, About 25% to about 30% acetone, and about 1% to about 5% water).

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  Examples of polymers for the solid dispersion include one or more water-soluble polymer (s) or partially water-soluble polymer (s). Water-soluble or partially water-soluble polymers include cellulose derivatives (eg, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol ( PVA); acrylates such as polymethacrylates (e.g. Eudragit <(R)> E); cyclodextrins (e.g. [beta] -cyclodextrin), and these including, e.g. PVP-VA (polyvinylpyrrolidone-vinyl acetate) Copolymers and derivatives include, but are not limited to.

  In some preferred embodiments, the polymer is hydroxypropyl methylcellulose (HPMC), such as HMPC60SH50, HPMC E50, or HPMC E15.

  In some embodiments, the polymer is a pH dependent enteric polymer. Examples of such pH-dependent enteric polymers include cellulose derivatives (eg, cellulose acetate phthalate (CAP)), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or salts thereof. (For example, sodium salts such as (CMC-Na)), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP) ), Or polymethacrylate (e.g., Eudragit <(R)> S), But it is not limited to these.

  In some preferred embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS), such as HMPC AS-HG.

  In another embodiment, the polymer (s) is an insoluble cross-linked polymer, such as polyvinylpyrrolidone (eg, crospovidone).

  In another embodiment, the polymer (s) is polyvinyl pyrrolidone (PVP).

  In some embodiments, the polymer is a mixture of two or more polymers (eg, a combination of two cellulosic polymers such as HPMC and HPMCAS).

  In some embodiments, the polymer (s) is present in the solid dispersion in an amount from about 30% to about 70% by weight.

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

In another aspect, the present disclosure provides:
a) making or producing a solution of VX-950, a cellulosic polymer and a solvent, wherein the solvent comprises at least one non-volatile solvent component (eg, glacial acetic acid);
b) providing a process for preparing a solid dispersion of VX-950 comprising spray drying the mixture to produce a solid amorphous dispersion comprising VX-950 and a cellulosic polymer;

  In some embodiments, the polymer is HPMC, HPMCAS, or a mixture thereof. In some preferred embodiments, the polymer is HPMCAS or a mixture of HPMC and HPMCAS.

  Examples of suitable volatile solvents include those that dissolve or suspend the drug alone or in combination with other co-solvents. In some preferred examples, the solvent or combination of solvents completely dissolves the drug.

  Examples of volatile solvents include methylene chloride, acetone, chloroform and THF.

  Examples of non-volatile solvents include organic acids such as glacial acetic acid, DMSO, DMF or water.

  In some embodiments, the non-volatile solvent is a component of a solvent system. For example, the non-volatile solvent may comprise from about 1% to about 20% (eg, from about 3% to about 15%, from about 4% to about 12%, or about 5% by weight as a component in the solvent. % To about 10% by weight).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination such as methylene chloride and acetone and a non-volatile solvent such as glacial acetic acid. For example, the solvent system may comprise about 40% to about 80% methylene chloride, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (eg, about 50% to about 70% methylene chloride, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

  In some preferred embodiments, the solvent system is a combination of a volatile solvent or combination of solvents such as methylene chloride and acetone and a non-volatile solvent such as water. For example, the solvent system can include from about 40% to about 80% methylene chloride, from about 20% to about 35% acetone, and from about 0.1% to about 15% water (eg, from about 50% to about 70% methylene chloride, About 25% to about 30% acetone, and about 1% to about 5% water).

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  In some embodiments, the solvent comprises a mixture of methylene chloride, acetone, and glacial acetic acid.

In another aspect, the present disclosure provides:
a) making or producing a mixture of VX-950, at least one cellulosic polymer and a solvent, wherein said solvent comprises glacial acetic acid;
b) providing a process for preparing a solid dispersion of VX-950 comprising spray drying the mixture to make a solid dispersion comprising VX-950;

  In some embodiments, the polymer is HPMC, HPMCAS, or a mixture thereof. In some preferred embodiments, the polymer is HPMCAS or a mixture of HPMC and HPMCAS.

  In some embodiments, the solvent also includes a volatile solvent or combination of solvents that dissolves or suspends the drug and polymer. In some preferred examples, the solvent or combination of solvents completely dissolves the drug and polymer.

  In some preferred embodiments, the solvent comprises a mixture of methylene chloride and acetone.

  In some embodiments, the glacial acetic acid, as a component in the solvent, is about 1% to about 20% by weight (eg, about 3% to about 15%, about 4% to about 12%, Or about 5% to about 10% by weight).

  In some embodiments, the solvent comprises a mixture of methylene chloride, acetone, and glacial acetic acid.

  In some embodiments, the solvent system comprises about 40% to about 80% methylene chloride, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (eg, about 50% to about 70%). % Methylene chloride, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

  In some preferred embodiments, the solvent system comprises from about 40% to about 80% methylene chloride, from about 20% to about 35% acetone, and from about 0.1% to about 15% water (eg, from about 50% About 70% methylene chloride, about 25% to about 30% acetone, and about 1% to about 5% water).

  In some embodiments, the mixture also includes a surfactant, such as sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof (eg, vitamin E TPGS).

  In one aspect, the present disclosure also provides an article made by the process described herein. For example, a solid dispersion of a drug (eg, VX-950), eg, an amorphous solid dispersion of a drug (VX-950). For example, an amorphous solid dispersion comprising a drug (eg, VX-950) and at least one polymer and optionally one or more solubility enhancing surfactants (eg, SLS or vitamin E TPGS) is provided. . The dispersion can improve the water solubility and bioavailability of the drug (eg, VX-950) when the solid dispersion is orally administered to a mammal (eg, rat, dog or human). In certain embodiments, at least a portion (eg, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, of the drug (eg, VX-950) in the solid dispersion, At least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%) is in an amorphous state. In preferred embodiments, the solid dispersion is essentially or substantially free of crystalline drug (eg, VX-950).

  As will be appreciated, spray drying can be performed in the presence of an inert gas. In certain embodiments, processes involving spray drying can be performed in the presence of a supercritical fluid comprising carbon dioxide or a mixture of carbon dioxide.

  "Low solubility drug" as used herein means a drug that is essentially completely water insoluble or less water soluble. This term applies to any beneficial therapeutic agent whose ratio of dose (mg) to water solubility (mg / mL) is greater than 100 mL, where the solubility of the drug is its neutrality in unbuffered water. The solubility of the form (eg free base or free acid). This definition includes, but is not limited to, drugs that are essentially not water soluble (less than 1.0 μg / mL).

  The cited patents, patent applications, and references are hereby incorporated by reference in their entirety. In case of conflict, the present application will take priority.

  The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Other features, objects, and advantages of the disclosure will be apparent from the description and the claims.

(Detailed explanation)
In general, the absolute bioavailability after oral administration of VX-950 micronized crystalline drug powder to rats was found to be less than 0.5%. A simple mixture of VX-950 and conventional pharmaceutical excipients exhibits similarly low bioavailability when administered orally to mammals. A composition comprising a crystalline form of VX-950 (ie, where a significant portion of VX-950 is in crystalline form) generally does not achieve drug absorption sufficient to provide a sufficient therapeutic effect of VX-950. . The compositions described herein provide relatively improved bioavailability. Accordingly, in some embodiments, a preparation of amorphous VX-950 is provided. For example, a purified preparation is described that is substantially free of impurities such as crystalline VX-950. In some embodiments, the present disclosure includes a pharmaceutical composition in the form of a solid dispersion comprising VX-950. The compositions of the present disclosure are stable, easy to administer, and provide high bioavailability of VX-950 upon administration.

  In certain embodiments, the VX-950 is about 5% to about 95%, such as about 30% to about 90%, preferably about 55% or less (eg, 53% to 57%). % By weight), about 60% by weight or less (eg, 58% to 62% by weight), about 65% by weight or less (eg, 63% to 67% by weight), about 70% by weight or less (eg, from 68% by weight) 72 wt%), about 75 wt% or less (eg, 73 wt% to 77 wt%), about 80 wt% or less (eg, 78 wt% to 82 wt%), about 85 wt% or less (eg, 83 wt%) To 87% by weight), or about 90% by weight or less (eg, 88% to 92% by weight). Said VX-950 is a mixture of D-isomer and L-isomer or a substantially pure product of either isomer. The VX-950 is preferably substantially amorphous (eg, at least about 50% of VX-950 is amorphous, at least about 55% of VX-950 is amorphous, At least about 60% of VX-950 is amorphous, at least about 65% of VX-950 is amorphous, at least about 70% of VX-950 is amorphous, at least about VX-950 About 75% is amorphous, at least about 80% of VX-950 is amorphous, at least about 85% of VX-950 is amorphous, at least about 90% of VX-950 is non-crystalline Crystalline, at least about 95% of VX-950 is amorphous, at least about 98% of VX-950 is amorphous, at least about 99% of VX-950 is amorphous, Or VX-950 substantially All is amorphous).

  As used herein, “amorphous” refers to a solid material that does not have long range order at the position of its atoms. In general, an amorphous solid is a supercooled liquid in which molecules are randomly arranged, lack a well-defined arrangement, and do not have long-range order. In general, amorphous solids are isotropic, that is, exhibit similar properties in all directions and do not have a definite melting point. For example, an amorphous material is a solid material that does not have a sharp characteristic crystal peak (s) in its X-ray powder diffraction (XRPD) pattern (ie, is not crystalline as determined by XRPD). Instead, one or several broad peaks (eg halos) appear in the XRPD pattern. A broad peak (eg, halo) is characteristic of an amorphous solid. See US 2004/0006237 for a comparison of XRPD between amorphous and crystalline materials.

  As used herein, “crystalline solid” refers to a compound or composition in which structural units are arranged in a regular geometric pattern or lattice, so that a crystalline solid exhibits a strict long-range order. Have. The units constituting the crystal structure can be atoms, molecules or ions. Crystalline solids exhibit a distinct melting point.

  As used herein, “dispersion” refers to a dispersion in which one substance (its dispersed phase) is distributed in discrete units throughout another substance (continuous phase or vehicle). The size of the dispersed phase can vary widely (eg, colloidal particles from nanometer to many microns in size). In general, the dispersed phase may be a solid, a liquid, or a gas. In the case of a solid dispersion, the dispersed phase and the continuous phase are both solid. For pharmaceutical applications, the solid dispersion may contain a crystalline drug (dispersed phase) in the amorphous polymer (s) (continuous phase) or non-crystalline in the amorphous polymer (continuous phase). May contain crystalline drug (dispersed phase). In some embodiments, the amorphous solid dispersion comprises the polymer (s) that make up the dispersed phase (and optionally a surfactant), and the drug makes up the continuous phase.

  The term “amorphous solid dispersion” generally refers to two or more components (usually drugs and polymers (or multiple polymers)), but possibly other components such as surfactants or other pharmaceutical additives. Solid dispersion), in which case the drug is in an amorphous phase, the physical stability and / or dissolution and / or solubility of the amorphous drug being determined by other components Is improved by.

  The solid dispersion provided herein is a particularly preferred embodiment of the present disclosure. Solid dispersions generally include compounds dispersed in a suitable carrier medium such as a solid carrier. In some embodiments, a carrier of the present disclosure comprises a polymer (eg, a water soluble polymer or a partially water soluble polymer). Preferably, in some embodiments, the carrier comprises a number of polymers, preferably one or more water soluble polymers or one or more partially water soluble polymers or combinations thereof.

  An exemplary solid dispersion is a coprecipitate or co-melt of VX-950 and a number of polymers. A “co-precipitate” is the product after dissolving a drug and a number of polymers in a solvent or solvent mixture followed by removal of the solvent or solvent mixture. Sometimes the mixture of polymers can be suspended in a solvent or solvent mixture. Examples of the solvent or solvent mixture include organic solvents and supercritical fluids. The solvent or solvent mixture may contain a non-volatile solvent such as glacial acetic acid or water. A “co-melt” is a mixture of drug and polymer (s), optionally heated in the presence of a solvent or solvent mixture, followed by mixing, and optionally removing at least a portion of the solvent. The product after cooling to room temperature at a selected rate. Optionally, the solid dispersion is prepared by adding a solution of drug and solid polymer followed by mixing to remove the solvent or solvent mixture. Vacuum drying, spray drying, tray drying, freeze drying, and other drying procedures can be applied to remove the solvent or solvent mixture. By applying any of these methods using suitable processing parameters in accordance with the present disclosure, the final solid dispersion product can be supplied with VX-950 in an amorphous state.

Preparation of Amorphous VX-950 For example, as described in US Patent Application Publication No. 2003/0186952 (see the literature cited therein in paragraph 1092) and US Patent Application Publication No. 2003/0185891. Any method for obtaining amorphous forms and solid dispersions can be used in connection with the present disclosure, including those that are present. In general, methods that can be used include those involving rapid removal of solvent or solvent mixture from the mixture or cooling of the molten sample. Such methods include, but are not limited to, rotary evaporation, freeze drying (ie freeze drying), vacuum drying, melt solidification, and melt extrusion. However, a preferred embodiment of the present disclosure involves an amorphous solid dispersion obtained by spray drying. Accordingly, in another embodiment, the present disclosure provides for drying the product obtained by spray drying to remove the solvent or solvent mixture.

  The preparations disclosed herein, for example pharmaceutical compositions, can be obtained by spray drying a mixture comprising VX-950, a number of suitable polymers and a suitable solvent or solvent mixture. Spray drying involves, for example, atomization of a liquid mixture containing a solid and a solvent or solvent mixture and removal of the solvent or solvent mixture. The solvent or solvent mixture may also contain non-volatile solvents such as glacial acetic acid. Atomization can be carried out, for example, with two liquids or pressure or an electronic nozzle or with a rotating disk.

  Spray drying converts the liquid feed into a dry granular form. Optionally, secondary drying processes such as fluid bed drying or vacuum drying can be used to reduce residual solvent (and other additives such as glacial acetic acid) to pharmaceutically acceptable levels. In general, spray drying involves contacting a highly dispersed suspension or solution (eg, the solution to be atomized) with a sufficient volume of hot air or gas (eg, nitrogen, eg, pure nitrogen) to cause evaporation, And drying of the droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion or paste that can be atomized using a selected spray drying apparatus. Standard procedures evaporate the solvent and spray the preparation into a stream of warm filtered air (or into a gas such as nitrogen) that carries the dried product to a collector (eg, a cyclone). The spent air or gas is then discharged with a solvent (or a solvent mixture containing any additive such as glacial acetic acid) (eg, then filtered) or the spent air or gas is sent to a cooler The solvent or solvent mixture is trapped and optionally recycled. For example, if a gas (eg, nitrogen) is used, the gas is then optionally recycled, heated again, and returned to the unit device in the closed loop system. Spray drying may be performed using a commercially available type of apparatus. For example, commercial spray dryers are available from Buchi Ltd. Manufactured by Niro (PSD series spray dryers manufactured by Niro) (see US Patent Application Publication Nos. 2004/0105820 and 2003/0144257).

  Spray drying generally uses about 1% to about 30%, or 50% or less, preferably at least about 10% solid loading of the material (ie, excipient in addition to drug). In some embodiments, a solid loading of less than 10% can result in poor yields and unacceptably long operating times. In general, the upper limit of solid loading depends on the resulting viscosity of the solution (eg, pumping ability) and the solubility of the components in the solution. In general, the viscosity of the solution can determine the size of the particles in the resulting powder product.

  Techniques and methods for spray drying are described in Perry's Chemical Engineering Handbook, 6th Ed. , R. H. Perry, D.C. W. Green & J. O. Maloney, eds. McGraw-Hill Book Co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. It can be found in Series 2 (1954). Generally, the spray drying is from about 40 ° C to about 200 ° C, such as from about 70 ° C to about 150 ° C, preferably from about 40 ° C to about 60 ° C, from about 50 ° C to about 55 ° C, or from about 80 ° C to about 110 ° C. C., for example, at an inflow temperature of about 90.degree. Spray drying is generally from about 20 ° C to 100 ° C, such as from about 25 ° C to about 30 ° C (eg, about 26 ° C), from about 40 ° C to about 50 ° C, from about 50 ° C to about 65 ° C, such as about 56 ° C. It is carried out at a discharge temperature of ℃ or about 58 ℃.

  Removal of the solvent or solvent mixture can be accomplished by subsequent drying steps such as tray drying, fluid bed drying (eg, from about room temperature to about 100 ° C.), vacuum drying, microwave drying, rotary drum drying, or bicone vacuum drying ( For example, approximately room temperature to approximately 200 ° C.) may be required.

  We have a direct relationship between bulk density / flow and residual solvent (s), with higher bulk density / better flow, more residual solvent (s). I found It would be advantageous to optimize powder flow and bulk density and use secondary drying to remove residual solvent or solvent mixture. In one embodiment of the present disclosure, the solid dispersion is fluid bed dried. Fluid bed drying at about 75 ° C. for about 8 hours has been found to be effective in certain embodiments to provide optimal effect with certain solid dispersions of VX-950. In other embodiments, for example using HPMCAS for a number of polymers in a solid dispersion, fluid bed drying at 45 ° C. for about 4 hours was effective to provide an acceptable residual solvent level in the final product. .

  In a preferred process, the solvent comprises a volatile solvent. In some embodiments, the solvent comprises a mixture of volatile solvents. Preferred solvents include those that can dissolve both VX-950 and the polymer. Suitable solvents include those described above, such as methylene chloride, acetone and the like. In a further preferred process, the solvent is a mixture of methylene chloride and acetone. The weight percent ratio of methylene chloride: acetone can be, for example, about 100: 0, about 90:10, about 80:20, about 70:30, about 60:40, preferably about 80:20 or about 70 : 30. The solvent or solvent mixture may also contain non-volatile solvents such as glacial acetic acid. The organic acid or polar solvent can be, for example, no more than about 5%, no more than about 10%, or no more than about 15% by weight of the solvent mixture. For example, the solvent mixture can contain a weight percent ratio of methylene chloride: acetone: glacial acetic acid of about 67: 28: 5 or 63:27:10. Although alcoholic solvents may be used in connection with the present disclosure, it has been found that alcohols react with VX-950 to form ketals. Accordingly, a solvent that does not react with VX-950 (particularly, does not react with VX-950 to form a ketal) is preferred. Such solvents should not contain OH groups or similar reactive moieties. Accordingly, preferred solvents in these processes are other than alcohols.

  Due to the reactivity of VX-950, preferred polymers for use with many polymers in connection with the present disclosure are other than polyethylene glycol (eg, PEG 8000) (ie, other than a polymer having a free hydroxyl moiety).

  The particle size and drying temperature range can be varied to prepare an optimal solid dispersion. As will be appreciated by those skilled in the art, a small particle size will lead to improved solvent removal. However, Applicants have discovered that smaller particle sizes result in splattered particles that do not result in a solid dispersion of VX-950 that is optimal for downstream processing such as tableting. At higher temperatures, crystallization or chemical degradation of VX-950 can occur. At lower temperatures, a sufficient amount of solvent (s) cannot be removed. The method herein provides optimal particle size and optimal drying temperature. In addition, Applicants have discovered that larger, more dense, and more fluid particles can be obtained by the addition of a non-volatile solvent, such as glacial acetic acid, to the solvent or solvent mixture. Such particles would be better suited for downstream processes, such as compression into tablets.

Provided herein is a solid dispersion comprising polymer VX-950 and a number of polymers (or solid support (s)). A polymer mixture of multiple polymers can be used with the drug as part of the amorphous solid dispersion system. Without being bound by theory, the presence of a large number of polymers aids in preventing the crystallization of the drug, reducing its amount or rate, or slowing down compared to the amount or rate of crystallization that occurs in the absence of the polymer. be able to. For example, using a large number of polymers, the amount of crystallization is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about at least about the amount of crystallization compared to the amount of crystallization in the absence of polymer. It can be reduced by 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. For example, many polymers can protect drugs from crystallization in aqueous media such as gastric fluid and / or intestinal fluid. For example, HPMC can help reduce the amount of crystallization (eg, of VX-950) at low pH, eg, in gastric fluid. HPMC can provide protection in gastric fluid (eg, fasting or fed gastric fluid) and artificial gastric fluid (“SGF”) (eg, fasting or fed SGF). As another example, HPMCAS can provide increased physical stability and intestinal fluid (eg, fasting or fed intestinal fluid) and artificial intestinal fluid (“SIF”) (eg, fasting or fed) The amount of crystallization (e.g. of VX-950) in (SIF) can be reduced. As a result, one or more of VX-950's bioavailability, solubility and absorption can be improved. In addition, due to the decrease in crystallization rate, many polymers may improve the storage stability of compositions containing VX-950, such as spray-dried dispersions or solid forms (eg, tablets) when no polymer is used. At least about 10% (eg, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, relative to the stability of the product, Or at least about 90%). The large number of polymers (eg when stored at 4 ° C. or at room temperature) compared the stability of the solid dispersion to a solid dispersion stored under the same conditions and in the absence of polymer, Increase by at least about 10% (eg, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) be able to.

  Further, without being bound by theory, the presence of multiple polymers prevents the crystallization of the drug and reduces the amount or rate of crystallization compared to the amount or rate of crystallization that occurs when one polymer is present. Or it can promote slow speed. For example, when multiple polymers are used, the amount of crystallization is at least about 10%, at least about 20%, at least about 30%, at least about 40% compared to the amount of crystallization when one polymer is present. , At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. For example, many polymers can protect drugs from crystallization in aqueous media such as gastric juice or intestinal fluid. For example, a mixture of a number of polymers, such as HPMC and HPMCAS, can provide increased protection of a given dispersion of VX-950, for example, HMPC can undergo VX- from crystallization in gastric juice or SGF. 950 can be protected, while HPMCAS can protect VX-950 from crystallization in intestinal fluid or SIF. As a result, the use of the mixture can result in improved bioavailability, solubility and / or absorption of VX-950. In addition, a number of polymers can increase the storage stability of compositions containing VX-950, such as solid forms (eg, spray-dried dispersions, tablets), to the stability of the composition when using one polymer. Compared to at least about 10% (eg, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% ) Can be increased. The large number of polymers compares the stability of the solid dispersion (eg when stored at 4 ° C. or at room temperature) to a solid dispersion containing one polymer stored under the same conditions. At least about 10% (eg, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) Can be increased.

  Using multiple polymers (eg, containing one or more cellulosic polymers), the area under the curve (AUC) of VX-950 is substantially the same in fasted and fed subjects when administered. For example, a form of VX-950 can be generated that reduces or substantially eliminates the food effect in the subject.

In one embodiment, the multiple polymers of the present disclosure or one or more of the multiple polymers can be dissolved in an aqueous medium. The solubility of the polymer (s) may not be pH dependent or may be pH dependent. The latter includes one or more enteric polymers. The term “enteric polymer” is a polymer that is preferentially soluble in a low intestinal acidic environment compared to the strongly acidic environment of the stomach, eg, insoluble in acidic aqueous media, but having a pH above 5-6. Sometimes refers to a polymer that is soluble. Suitable polymers must be chemically and biologically inert. In order to improve the physical stability of the solid dispersion, the glass transition temperature (T _g ) of the polymer (eg, of multiple polymers, or one or more of the multiple polymers) is as high as possible. I have to. For example, preferred polymers have a glass transition temperature that is at least equal to or higher than the glass transition temperature of the drug (eg, VX-950). Other preferred polymers have a glass transition temperature within about 10 to about 15 ° C. of the drug (eg, VX-950). Examples of suitable glass transition temperatures for the polymer include (measured under dry conditions) at least about 90 ° C, at least about 95 ° C, at least about 100 ° C, at least about 105 ° C, at least about 110 ° C, at least about 115 ° C, At least about 120 ° C, at least about 125 ° C, at least about 130 ° C, at least about 135 ° C, at least about 140 ° C, at least about 145 ° C, at least about 150 ° C, at least about 155 ° C, at least about 160 ° C, at least about 165 ° C, At least about 170 ° C, at least about 175 ° C. While not wishing to be bound by theory, the underlying mechanism is that polymers with higher T _g have a higher molecular mobility at room temperature (this is in stabilizing the physical stability of amorphous solid dispersions). It can be a very important factor).

In addition, the hygroscopicity of the polymer (s) should be as low as possible (eg, of multiple polymers, or one or more of the multiple polymers). For comparison in this application, the hygroscopicity of a polymer, polymer combination, or composition is characterized by a relative humidity of about 60%. In some preferred embodiments, the polymer has a water absorption of less than about 10%, such as less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, about 4%. Less than, less than about 3%, or less than about 2% water absorption. Cellulosic polymers generally have a water absorption of about 3%, whereas PVP generally has a water absorption of about 9%. Hygroscopicity can also affect the physical stability of the solid dispersion. Generally, moisture absorbed in the polymer, it is possible to lower the T _g of the polymers thereof and consequently resulting solid dispersion large, this is the physical stability of the solid dispersion as described above Will be further reduced.

  In some embodiments, the multiple polymers, or one or more polymers of the multiple polymers, are one or more water soluble polymers or partially water soluble polymers. Water-soluble or partially water-soluble polymers include cellulose derivatives (eg, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol ( PVA); acrylates such as polymethacrylates (eg Eudragit® E); cyclodextrins (eg β-cyclodextrin), and eg PVP-VA (polyvinylpyrrolidone-vinyl acetate), PVP K30 (polyvinylpyrrolidone) These copolymers and derivatives include, but are not limited to: In some preferred embodiments, one of the multiple polymers is hydroxypropyl methylcellulose (HPMC), such as HPMC E50 (eg, from Dow), HPMC E15 or HPMC 60SH 50cP (eg, Shin-Etsu Chemical). (Metalose, HPMC60SH50 manufactured by Shin-Etsu). HPMC is available in various types from Shin-Etsu Chemical Co., Ltd., including SM, 60SH, 65SH, and 90SH. Each of these types differ in viscosity grade and methoxyl and hydroxypropyl content. The most preferred type for use in the spray dispersion is HPMC 60SH.

  In some embodiments, the multiple polymers, or one or more of the multiple polymers, is a pH dependent enteric polymer. Examples of such pH-dependent enteric polymers include cellulose derivatives (eg, cellulose acetate phthalate (CAP)), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or salts thereof. (E.g., sodium salts such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP) Or polymethacrylate (eg Eudragit® S), But it is not limited to these. In some preferred embodiments, one of the many polymers is hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS is available in various grades from Shin-Etsu Chemical Co., Ltd., including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, and AS-HG. Each of these grades depends on the substitution rate of acetate and succinate. The most preferred grade for use in the spray dispersion is AS-HG from Shin-Etsu Chemical Co., Ltd.

  In yet another embodiment, one or more of the multiple polymers is an insoluble crosslinked polymer, such as polyvinylpyrrolidone (eg, crospovidone).

  In embodiments where a drug, such as VX-950 with HPMC and / or HPMCAS polymer, forms a solid dispersion with multiple polymers, the total amount of polymer relative to the total weight of the solid dispersion is generally at least about 5% ( For example, about 4% or 6%), at least about 10% (eg, about 9% or 11%), at least 15% (eg, 14% or 16%), at least 20% (eg, 19% or 21%) And preferably at least about 30% (eg, about 29% or about 31%), such as at least about 35% (eg, about 34% or 36%), at least 40% (eg, about 39% or 41%) , At least 45% (eg, about 44% or 46%), or at least 50% (eg, 49% or 51%). The amount is generally about 99% or less, and preferably about 80% or less, for example about 75% or less, about 70% or less, about 65% or less, about 60% or less, or about 55% or less. In one embodiment, the polymer is in an amount of no more than about 30% (and even more particularly, between about 28% and about 32%, such as 29%) of the total weight of the dispersion. In one embodiment, the polymer is in an amount of no more than about 35% (and more particularly between about 33% and about 37%, such as 34%) of the total weight of the dispersion. In one embodiment, the polymer is in an amount of about 40% or less (and even more particularly between about 38% and about 42%, such as 39%) of the total weight of the dispersion. In one embodiment, the polymer is in an amount of about 45% or less (and even more particularly between about 43% and about 47%, such as 44%) of the total weight of the dispersion.

  A solid (eg, spray dried) dispersion containing VX-950 may contain a number of polymers. For example, two polymers can be used in the dispersion. In some embodiments, the multiple polymers may include one or more than one cellulosic polymer. For example, the spray-dried dispersion may contain two cellulosic polymers, such as HPMC and HPMCAS. In some embodiments, the solid dispersion may comprise a mixture of HPMC and HPMCAS. The amount of each polymer used in the dispersion can vary, and the ratio of those polymers to each other can also vary. For example, the dispersion may comprise about 0% to 100% by weight of a first polymer (eg, HPMC) and about 0% to about 100% by weight of a second polymer (eg, HPMC AS). (In this case, the weight percentages of these two polymers add up to 100% of the total polymer present in the dispersion). For example, in a solid dispersion of VX-950 containing a polymer, the first polymer is present in an amount of about 33% of the total amount of polymer added and the second polymer is present in an amount of about 67%. To do. In another example, the first polymer is present in an amount of about 55.5% of the total amount of polymer added and the second polymer is present in an amount of about 44.5%. In another example, the first polymer is present in an amount of about 63% of the total amount of polymer added and the second polymer is present in an amount of about 37%. In another example, the first polymer is present in an amount of about 50% of the total amount of polymer added and the second polymer is present in an amount of about 50%. In another example, the first polymer is present in an amount of about 100% of the total amount of polymer added and the second polymer is present in an amount of about 0%.

  In one more specific embodiment of the present disclosure, one of the polymers is polyvinylpyrrolidone (PVP) (eg, PVP 29/32). The PVP may be present in an amount of about 35% or less, about 40% or less, about 45% or less, or about 50% or less. Dispersions comprising about 50% (eg, about 49.5%) PVP K29 / 32 are encompassed by the present disclosure.

  In another embodiment, the present disclosure includes a solid dispersion of VX-950 and at least two cellulosic polymers, such as HPMC and / or HPMCAS polymers. In some preferred embodiments, the drug (ie, VX-950) is at least about 50% of the dispersion, such as at least about 55%, at least about 60%, at least about 65%, at least about 70%, It is present in an amount of at least about 75%, at least about 80%, at least about 85%, at least about 90%, or even greater. In some preferred embodiments, the drug is present in an amount between about 55% and about 70%, such as about 55%, about 60%, about 65%, or about 70%. As explained above, the total amount of polymer is at least about 15%, and preferably at least 20%, such as at least 25%, at least 30%, at least 35%, at least 40%, or at least about 45%. Exists. In some embodiments, this amount is generally about 55% or less, and preferably about 50% or less, such as about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25%. % Or less, about 20% or less, about 15% or less, or about 10% or less.

  In some preferred embodiments, the dispersion further comprises other minor components, such as a surfactant (eg, SLS or Vitamin E TPGS). In some preferred embodiments, the surfactant is less than about 10% by weight of the dispersion, such as less than about 9%, less than about 8%, less than about 7%, less than about 6%, It is present at less than about 5%, less than about 4%, less than about 3%, less than about 2%, or about 1% by weight.

  The multiple polymers must be present in an effective amount to stabilize the solid dispersion. Stabilization includes inhibition or reduction of crystallization of VX-950. Such stabilization would inhibit the conversion of VX-950 from the amorphous form to the crystalline form. For example, the polymer can be at least a portion of VX-950 (eg, about 5%, about 10%, about 15%, about%, about 20%, about 25%, about 30%, about 35%, about 40%, About 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more) will prevent progression from the amorphous form to the crystalline form. Let's go.

  For example, at low pH (eg, in gastric fluid (eg, fasting gastric fluid) or SGF (eg, fasting SGF)), VX-950 can dissolve, become supersaturated, and then crystallize. The multiple polymers can prevent or reduce crystallization of VX-950 in such or similar conditions, or during storage of compositions containing VX-950. For example, stabilization can be measured by measuring the glass transition temperature of the solid dispersion, by measuring the relaxation rate of the amorphous material, or by measuring the solubility or bioavailability of VX-950.

A number of polymers can be used in formulations with VX-950. For example, one, more than one, or all polymers suitable for use with VX-950 to form a solid dispersion, such as an amorphous solid dispersion, have one of the following properties: Must have more than one:
1. The glass transition temperature of the polymer in combination must have a temperature that is about 10-15 ° C. or more lower than the glass transition temperature of VX-950. Preferably, the glass transition temperature of the polymer in combination is higher than the glass transition temperature of VX-950, generally at least 50 ° C. higher than the desired storage temperature of the drug product. For example, at least 100 ° C, at least 105 ° C, at least 105 ° C, at least 110 ° C, at least 120 ° C, at least 130 ° C, at least 140 ° C, at least 150 ° C, at least 160 ° C, at least 160 degrees, or higher.

  2. The polymer in combination must be relatively non-hygroscopic. For example, the polymer may contain about 10% or more water, such as about 9% or more, about 8% or more, about 7% or more, about 6% or more, about 5% or more, when stored under standard conditions. It must not absorb more than 4% or about 3% water. Preferably, the polymer will be substantially free of water when stored under standard conditions.

  3. The polymer in combination must have a solubility in a solvent suitable for the spray drying process similar to or better than that of VX-950. In a preferred embodiment, the polymer will be dissolved in one or more of the same solvents or solvent systems as VX-950. The polymer is preferably soluble in at least one non-hydroxy containing solvent, such as methylene chloride, acetone or combinations thereof.

  4). For example, when used in combination with VX-950 in a solid dispersion, the polymer in combination is compared to the solubility of VX-950 in the absence of polymer or compared to the solubility of VX-950 in combination with a reference polymer. Thus, the solubility of VX-950 in aqueous and physiologically relevant media must be increased. For example, the polymer can increase the solubility of amorphous VX-950 by reducing the amount of amorphous VX-950 that is converted from solid amorphous dispersion to crystalline VX-950.

  5). The polymer in combination must reduce the relaxation rate of the amorphous material.

  6). The polymer in combination must increase the physical and / or chemical stability of VX-950.

  7. The polymer in combination must improve the manufacturability of VX-950.

  8). The polymer in combination must improve one or more of the handling, administration or storage properties of VX-950.

  9. The polymer in combination should not adversely interact with other pharmaceutical ingredients such as excipients.

  The suitability of a candidate polymer (or other component) can be tested using the spray drying method (or other method) described herein to form an amorphous composition. Candidate compositions can be compared for stability, resistance to crystalline morphologies, or other properties, as well as reference preparations such as those described herein, eg, about 55% amorphous VX-950 and about 44% HPMC and / or HPMCAS (eg, a mixture of 24.4% HPMC and 19.6% HPMC AS; the percentage is a percentage of the total weight of the dispersion) and about 1 % Of a surfactant, for example a preparation with SLS or vitamin E TPGS, or crystalline VX-950. For example, a candidate composition can be tested to determine if it prevents the opportunity for solvent-mediated crystallization to occur, or at least 50%, 75%, 100% conversion at a given time under controlled conditions. As well as a reference preparation or candidate composition to determine if it has improved bioavailability or solubility compared to crystalline VX-950. You may judge.

  A particularly preferred embodiment comprises a solid dispersion of VX-950, HPMC, HPMCAS and surfactant. For example, about 55% VX-950, between about 15% and about 25% (eg, about 19.6%) HPMC polymer, eg, HPMC 60SH50, and between about 20% and about 30% (eg, about 24.4%) solid dispersion comprising HPMCAS polymer, eg HPMCAS-HG, and about 1% surfactant, eg SLS.

  Another preferred embodiment is about 55% VX-950 and between about 25% and about 35% (eg, about 29.3%) HPMC polymer, eg, HPMC 60SH50, about 10% and about 20%. Between (eg, about 14.7%) HPMCAS polymer, eg, HPMCAS-HG, and about 1% surfactant, eg, SLS.

  Another preferred embodiment is about 60% VX-950 and between about 10% and about 20% (eg, about 14.6%) HPMC polymer, such as HPMC 60SH50, about 20% and about 30%. Between (eg, about 24.4%) HPMCAS polymer, eg, HPMCAS-HG, and about 1% surfactant, eg, SLS.

  Another preferred embodiment is about 65% VX-950 and between about 12% and about 22% (eg, about 17%) HPMC polymer, such as HPMC 60SH50, between about 12% and about 22%. A solid dispersion comprising (eg, about 17%) HPMCAS polymer, eg, HPMCAS-HG, and about 1% surfactant, eg, SLS.

  Another preferred embodiment is about 70% VX-950 and between about 15% and about 25% (eg, about 19.3%) HPMC polymer, such as HPMC 60SH50, about 5% and about 15%. Between (eg, about 9.7%) HPMCAS polymer, eg, HPMCAS-HG, and about 1% surfactant, eg, SLS.

Surfactants Solid dispersions, such as spray-dried dispersions, or other compositions may contain a surfactant. A surfactant or surfactant mixture will generally reduce the surface tension between the solid dispersion and the aqueous medium. A suitable surfactant or surfactant mixture can also improve the water solubility and bioavailability of VX-950 from a solid dispersion. Surfactants for use in connection with the present disclosure include sorbitan fatty acid esters (eg, Spans®), polyoxyethylene sorbitan fatty acid esters (eg, Tween®), sodium lauryl sulfate (SLS). ), Sodium dodecylbenzenesulfonate (SDBS), dioctyl sodium sulfosuccinate (docose), dioxycholic acid sodium salt (DOSS), sorbitan monostearate, sorbitan tristearate, hexadecyltrimethylammonium bromide (HTAB), N-lauroyl sarcosine Sodium, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, Gelucire 44/14, ethylenediaminetetraacetic acid (EDT) A), vitamin E or tocol derivatives such as alpha tocopherol (eg d-alpha tocopherol, dl-alpha tocopherol, tocopherol succinate) and tocopheryl esters such as tocopheryl acetate, tocopheryl succinate, eg vitamins Ed-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS; e.g. vitamin E TPGS from Eastman), lecithin, MW 677-692, monosodium glutamate monohydrate, Labrasol, PEG8 caprylic / capric glyceride, Transcutol, Diethylene glycol monoethyl ether, Solutol HS-15, polyethylene glycol / hydroxystearate , Taurocholic acid, Pluronic F68, Pluronic F108 and Pluronic F127 (or any other polyoxyethylene-polyoxypropylene copolymer (Pluronic®) or saturated polyglycolized glycerides (Gelucirs®)) However, it is not limited to these. Specific examples of such surfactants that can be used in connection with the present disclosure include Span 65, Span 25, Tween 20, Capryol 90, Pluronic F108, Sodium Lauryl Sulfate (SLS), Vitamin E TPGS, Pluronic Classes and copolymers, but are not limited to these. SLS (eg, Sigma or Fischer) and vitamin E TPGS are preferred.

  The amount of surfactant (eg, SLS or Vitamin E TPGS) relative to the total weight of the solid dispersion can be between about 0.1-20%. Preferably, it is from about 1% to about 20%, from about 1% to about 15%, from about 1% to about 10%, more preferably from about 1% to about 5%, such as about 1%, about 2% , About 3%, about 4%, or about 5%.

  In certain embodiments, the amount of surfactant relative to the total weight of the solid dispersion is at least about 0.1%, preferably at least about 0.5%, and more preferably at least about 1% (eg, about 1%). ). In these embodiments, the surfactant is about 20% or less, and preferably about 15%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%. , About 5%, about 4%, about 3%, about 2%, or about 1% or less. As shown in the examples herein, embodiments in which the surfactant is present in an amount of about 1% by weight are preferred.

  Candidate surfactants (or other components) can be tested for suitability for use in the present disclosure in a manner similar to that described for polymer testing.

Composition / Packaging / Use A pharmaceutical composition is also provided herein. The forms of VX-950 and solid dispersions of the present disclosure can be further processed to prepare a pharmaceutical composition for administration to a patient. A solid dispersion can be considered a pharmaceutical composition but may require further processing prior to administration (eg, the solid dispersion may be further formulated into tablets). All such pharmaceutical compositions, dosage forms, and pharmaceutical formulations (eg, sustained release or immediate release formulations) are intended to be encompassed by the present disclosure. The formulation can be prepared according to known methods using known ingredients (see Handbook of Pharmaceutical Excipients). As will be appreciated, oral formulations are often preferred for pharmaceutical administration.

  Accordingly, provided herein are pharmaceutical compositions comprising VX-950. Such compositions generally contain a pharmaceutically acceptable carrier, diluent or vehicle. In some embodiments, VX-950 is in an amorphous form. In some embodiments, VX-950 is in the form of a solid dispersion (eg, an amorphous solid dispersion). These VX-950 forms and dispersions are preferably prepared as disclosed herein.

  The compositions and processes of the present disclosure may optionally include one or more excipients (see USP 6,720,003, US 2004/0030151, and / or WO 99/02542). An excipient is a substance used as a carrier or vehicle in a dosage form, or a substance added to a pharmaceutical composition to improve handling, storage or preparation of the dosage form. Excipients include diluents, disintegrants, adhesives, wetting agents, lubricants, lubricants, crystallization inhibitors, surface modifiers, drugs for concealing or neutralizing unpleasant taste or odor, wearing Perfumes, pigments, fragrances, fillers, binders, stabilizers and materials that improve the appearance of the composition include, but are not limited to.

  Also provided herein is a process for preparing a formulation comprising amorphous form of VX-950 or a dispersion or composition thereof into a dosage form suitable for administration to a mammal. Preferably, the formulation comprises a solid dispersion prepared as described herein.

  Accordingly, another embodiment of the present disclosure provides a composition comprising VX-950 or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, VX-950 reduces viral load in a sample or in a patient (eg, reduces viral plasma levels by at least about 3 logs, at least about 4 logs, or at least about 5 logs). Present in a pharmaceutically acceptable carrier in an effective amount. Alternatively, the composition of the present disclosure includes another additional agent (eg, a CYP inhibitor) as described herein. Each component may be present in an individual composition, in a composite composition, or in a single composition.

  As used herein, the term “comprising” is intended to be able to vary depending on the situation, and thus indicates that it may optionally include other agents in addition to the specified drug.

  As used herein, compounds of the present disclosure, including VX-950, are defined to include their pharmaceutically acceptable derivatives or prodrugs. “Pharmaceutically acceptable derivative or prodrug” is any pharmaceutically acceptable compound of the present disclosure that is capable of (directly or indirectly) providing the compound of the present disclosure when administered to a recipient. Salt, ester, ester salt, or other derivative (eg, amide imido acid ester). Particularly preferred derivatives and prodrugs are those that provide bioavailability of the disclosed compounds (eg, by allowing easier absorption of orally administered compounds into the blood) when such compounds are administered to a mammal. Or increased delivery of the parent compound to the biological compartment (eg, liver, brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives in which a group that enhances water solubility or active transport through the intestinal membrane has been added to the structure of the formulas described herein.

  VX-950 utilized in the compositions and methods of the present disclosure can also be modified by adding appropriate functional groups to improve selective biological properties. Such modifications are known in the art and include modifications that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), modifications that increase oral availability, Modifications that increase solubility to allow administration by injection, modifications that alter metabolism, and modifications that alter excretion rates.

  Pharmaceutically acceptable carriers that can be used in these compositions include ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, Sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, trisilicate Examples include magnesium acid, polyvinyl pyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymer, polyethylene glycol and wool oil. But it is not limited to.

  The pharmaceutical compositions of the present disclosure may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, pills, powders, granules, aqueous suspensions or solutions. it can. In the case of tablets for oral use, carriers that are commonly used include lactose, microcrystalline cellulose, mannitol, dicalcium phosphate, calcium carbonate and corn starch. Lubricants such as magnesium stearate, sodium stearyl fumarate or stearic acid are also commonly added. Other ingredients may include disintegrants such as croscarmellose sodium or sodium starch glycolate; flow aids such as colloidal silica; and surfactants such as SLS and vitamin E. Diluents useful for oral administration in a capsule form include lactose, microcrystalline cellulose, mannitol, dicalcium phosphate, calcium carbonate and dried corn starch. Similar to the tablet formulations described above, capsule formulations may contain lubricants, disintegrants, surfactants or flow aids. In some embodiments, the tablets are coated with a film, for example, to increase ease of swallowing. An enteric coating can also be applied to the oral dosage form to control where the composition is absorbed in the digestive system (eg, the coating cannot dissolve at the acidic pH of the stomach but is higher in the small intestine). can be dissolved at pH). Examples of enteric coatings include methacrylic acid copolymer, cellulose acetate (and its succinate and phthalate versions), styrene maleic acid copolymer, polymethacrylic acid / acrylic acid copolymer, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxyethyl ethylcellulose phthalate, Hydroxypropyl methylcellulose acetate succinate, cellulose acetate tetrahydrophthalate, acrylic resin, trimellitate and shellac. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can also be added. Acceptable liquid dosage forms include emulsions, solutions, suspensions, syrups and elixirs.

  According to a preferred embodiment, the composition of the present disclosure is formulated for pharmaceutical administration to a mammal, preferably a human. The forms and dispersions of VX-950 provided herein are preferably formulated for oral administration, although other formulations can be obtained.

  Other pharmaceutical compositions of the present disclosure (as well as compositions for use in the disclosed methods, concomitant drugs, kits and packs) can be administered orally, parenterally, sublingually, by inhalation spray, topical administration, It can be administered by rectal administration, nasal administration, buccal administration, vaginal administration or in-plant reservoir. The term “parenteral” as used herein is subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Is included. Preferably, the composition is administered orally or intravenously.

  The disclosure also provides pharmaceutical packs and kits comprising amorphous VX-950, solid dispersions or pharmaceutical compositions of any embodiment herein.

  The present disclosure further provides a method for treating or preventing hepatitis C virus infection in a patient comprising administering to the patient a pharmaceutical composition. The pharmaceutical composition comprises any form of VX-950, any solid dispersion or any composition of the present disclosure.

  According to another embodiment, the present disclosure provides a method for treating a patient infected with a virus characterized by a virus-encoded NS3 / 4A serine protease, such as HCV, required for the viral life cycle, This method is by administering to the patient any form of VX-950, any solid dispersion or composition of the present disclosure. Preferably, the methods of the present disclosure are used to treat patients suffering from HCV infection. Such treatment may completely eradicate the viral infection or reduce its severity. More preferably, the patient is a human.

  In yet another embodiment, the present disclosure provides a method of pretreating a biological material scheduled for administration to a patient, the method comprising said biological material and a compound of the present disclosure. Contacting with a pharmaceutically acceptable composition. Such biological materials include blood and its components, such as plasma, platelets, and subpopulations of blood cells; organs such as the kidney, liver, heart, lung, etc .; semen and eggs; bone marrow and its components; and Other fluids that are injected into the patient, such as but not limited to saline, dextrose, and the like. In some embodiments, VX-950 can be placed on or in a device that is inserted into a patient.

  The pharmaceutical composition is prescribed to the patient in a “patient pack” containing more than one dose, preferably in the entire course of treatment, a single package (eg, a blister pack) You can also. Patient packs always include package inserts that patients have in their patient packs (typically not found in traditional prescription drugs) rather than traditional prescription drugs where the pharmacist divides the patient supply from the bulk supply. It is advantageous in that it can be used. Including package attachments has been shown to improve patient compliance with physician instructions. Preferably, the drug is an oral dosage form.

  It is a desirable further feature of the present disclosure that the package attachment that directs the patient to the correct use of the present disclosure includes the management of the combination of the present disclosure with a single patient pack or a patient pack for each formulation. That will be understood.

  According to a further aspect of the present disclosure, the pack includes at least an informational attachment containing instructions on the use of any form of VX-950, any solid dispersion or composition of the present disclosure, and the combination of the present disclosure. Including. In an alternative embodiment of the present disclosure, the pharmaceutical pack further comprises one or more of additional drugs as described herein. The additional drug (s) may be provided in the same pack or in a separate pack.

  Another aspect of this is that single or multiple pharmaceutical formulations of each pharmaceutical ingredient; containers that contain the pharmaceutical formulations thereof during storage and prior to administration; and for treating or preventing HCV infection Including packaged kits for inhibiting HCV or for patients to use in the treatment of HCV infection or prevention of HCV infection, including instructions for administering drugs in an effective manner. Preferably, the drug is an oral dosage form.

  Thus, the present disclosure provides kits for simultaneous or sequential administration of VX-950 (and optionally additional agents) or derivatives thereof, made in a conventional manner. In general, such kits include, for example, a composition of each inhibitor and optionally additional drug (s) in a pharmaceutically acceptable carrier (and in one or multiple pharmaceutical formulations), and Instructions for simultaneous or sequential administration will be included. Preferably the medicament is an oral dosage form.

  In another embodiment, one or more dosage forms (preferably oral dosage forms) for self-administration; preferably sealed containers for containing said dosage forms during storage or prior to use A packaged kit is provided that includes means; and instructions for a patient to perform drug administration. The instructions will generally be instructions written on package inserts, labels, and / or other components of the kit, and the dosage form (s) are as described herein. . Each dosage form may individually contain each dosage form, as in the case of a sheet of metal foil-plastic laminate having each dosage form isolated from each other in individual cells or bubbles, Or the dosage form may be contained in a single container, as in the case of plastic bottles or vials. In general, the kit will also include means for packaging the individual kit components, ie, the dosage form, container means, and instructions described for use. Such packaging means may take the form of cardboard or paper boxes, plastic or foil pouches and the like.

  Embodiments of the present disclosure may include additional agents. Accordingly, the disclosed methods may include steps such as administration of such additional agents.

Dosage A dosage level of about 0.01 to about 100 mg / kg body weight per day, preferably about 10 to about 100 mg / kg body weight per day, of VX-950 is useful for the prevention and treatment of HCV-mediated diseases. Useful. In some embodiments, the dosage level is about 0.4 to about 10 g / day, for example, about 1 to about 4 g / day per person (based on an average size of a person calculated to be about 70 kg), Preferably, from about 2 to about 3.5 g / day. In general, the pharmaceutical compositions of the present invention will be administered according to the present invention from about 1 to about 5 times per day, preferably from about 1 to about 3 times per day, or as a continuous infusion. In some embodiments, VX-950 is administered using a controlled release formulation. In some embodiments, this may help provide a relatively stable blood level of VX-950.

  In some embodiments, the dose of amorphous VX-950 is a standard dose, such as about 1 g to about 5 g per day, more preferably about 2 g to about 4 g per day, more preferably about 1 g per day. It can be from 2 g to about 3 g, such as from about 2.25 g to about 2.5 g per day. For example, a dose of about 2.25 g / day of amorphous VX-950 can be administered to a patient, for example, about 750 mg can be administered three times a day. Such doses can be administered, for example, as a 3 × 250 mg dose 3 times daily or as a 2 × 375 mg dose 3 times daily. In some embodiments, the 250 mg dose is in about 700 mg tablets. In some embodiments, the dose of about 375 mg is in about 800 mg tablet. As another example, a dose of about 2.5 g / day of amorphous VX-950 can be administered to a patient, for example about 1250 mg administered twice a day. As another example, about 1 g to about 2 g of amorphous VX-950 can be administered to a patient per day, for example, about 1.35 g of amorphous VX-950 is administered to a patient, for example Approximately 450 mg can be administered three times a day. This dose of amorphous VX-950 can be administered, for example, as a powder dry dispersion or as a tablet (eg, a tablet comprising VX-950, eg, VX-950 in a spray-dried dispersion).

  In some embodiments, a VX-950 solid (eg, spray dried) dispersion described herein is at least about 50%, at least about 55%, at least about 60%, at least about 65%, Contains at least about 70%, at least about 75%, at least about 80%, at least about 85%, or more VX-950 (eg, amorphous VX-950). These dispersions can contain a greater amount of VX-950 (eg, a greater weight percent of VX-950) for a given amount of dispersion, so the same amount of solids by weight In the case of dispersions, a greater amount of VX-950 can be incorporated into the pharmaceutical composition, resulting in an increased loading of the active ingredient in the composition. As a result, subjects receiving VX-950 can take a smaller dose of VX-950 and nevertheless take the same amount of drug. For example, to receive a 750 mg dose of VX-950, a subject may take a 2 × 375 mg dose of VX-950 containing a solid dispersion described herein instead of a 3 × 250 mg dose. Good. This is an improved or preferred dose for some patients. As another example, an increased loading of amorphous VX-950 in a solid dispersion allows a subject to be administered a larger dose of VX-950 with a fixed total dose of the pharmaceutical composition (eg, Standard size tablets can contain a larger percentage (and consequently dose) of amorphous VX-950). Conversely, an increased loading of amorphous VX-950 can allow a subject to be administered a fixed dose of amorphous dose with a lower total dose of the pharmaceutical composition (eg, a standard dose of amorphous VX- 950 can be administered in smaller tablets).

  In some embodiments, the amorphous VX-950 is not 100% potency and purity (eg, the potency or purity is at least about 90%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% potency), in which case the dose described above is the total amount of VX-950 Rather, it refers to the amount of efficacious or pure VX-950 administered to a patient. These doses can be administered as monotherapy and / or can be administered as part of a combination therapy, eg, as further described below.

  Such administration can be used as a chronic or acute phase treatment. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. A typical preparation will contain from about 5% to about 95% (w / w) of active compound. Preferably such preparations contain from about 20% to about 80%, from about 25% to about 70%, from about 30% to about 60% active compound.

  Where a composition or method of the present disclosure involves the combination of VX-950 and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent are doses that are normally administered in a monotherapy regimen. It should be present at a dosage level between about 10 and 100% of the amount, and more preferably between about 10 and 80%.

  Once the patient's condition has improved, a maintenance dose of a compound, composition or combination of the present disclosure can be administered as needed. Thereafter, the dosage or frequency of administration, or both, can be reduced in the context of the condition, for example, to about 1/2 or 1/4 or less of the dosage or frequency of administration, and the improved condition is retained If the symptoms are alleviated to the desired level, treatment is terminated. However, any recurrence of disease symptoms may require the patient to have intermittent treatment on a long-term basis.

  The specific dosage and treatment regimen for any particular patient should be the combination of specific compound activity, age, weight, overall health, sex, diet, number of doses, excretion rate, drug combinations utilized It should also be understood that this will depend on various factors, including the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient will also depend on the particular described compound and the presence or absence and nature of additional antiviral agents in the composition.

Combination Therapy Methods of the disclosure include: immunomodulators; antiviral agents; inhibitors of HCV protease; inhibitors of other targets in the HCV life cycle; ribosome internal entry inhibitors, broad spectrum virus inhibitors; another cytochrome P- Administration of additional components including additional agents selected from 450 inhibitors; or combinations thereof may also be included.

  Accordingly, in another embodiment, the present invention relates to any form of VX-950, any solid dispersion or composition of the present disclosure, a CYP inhibitor and another antiviral agent, preferably an anti-HCV agent. A method comprising the administration of Such antiviral agents include immunomodulators such as α-, β- and γ-interferons, PEGylated derivatized interferon-α compounds, and thymosins; other antiviral agents such as ribavirin, amantadine and terbivudine; others Other hepatitis C protease inhibitors (NS2-NS3 inhibitors and NS3 / NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicases, polymerases and metalloprotease inhibitors; ribosome internal entry inhibitors A broad spectrum virus inhibitor, eg, an IMPDH inhibitor (eg, US Pat. Nos. 5,807,876, 6,498,178, 6,344,465, 6,054,472); No .; International applications WO 97/40028, WO 98/4038 , Compounds of WO 00/56331, and mycophenolic acid and derivatives thereof, and including but not limited to VX-497, VX-148, and / or VX-944); or any combination of the above However, it is not limited to these.

  A preferred combination therapy is one dose of amorphous VX-950 as described herein, and interferon-α, such as PEGylated derivatized interferon-α (eg, PEGylated interferon-alpha-2a, such as PEGASYS®. ), Eg, at its standard dose; or PEGylated interferon-alpha-2b, eg, PEG-INTRON® (eg, REDIPEN PEG-INTRON®), eg, at its standard dose). For example, one dose of amorphous VX-950 (eg, as described above), eg, 2 to 3 g (eg, 2.5 g, 2.25 g), eg, three times a day, eg, in the form described herein. (Eg, 750 mg 3 times a day)), as well as PEGylated interferon-alpha-2a at its standard dose, eg, 180 μg once a week, subcutaneously, eg, for 48 weeks. can do. As another example, a dose of VX-950 can be administered with both PEGylated interferon-alpha-2 and ribavirin. For example, from about 2 g to about 3 g (eg, about 2.5 g, about 2.25 g (eg, 750 mg three times a day)) of the amorphous VX-950 described herein, For Type 1 patients, eg, 180 μg PEGylated interferon-alpha-2a (eg, PEGASYS®) once a week for 48 weeks and 1000-1200 mg / day ribavirin (eg, COPEGUS®) , REBETOL®) or in combination with 180 μg PEGylated interferon-alpha-2a + 800 mg / day ribavirin once a week for patients with genotype 2 or 3 hepatitis C can do.

  Each drug can be formulated in separate dosage forms. Alternatively, the respective drugs can be formulated together in any combination to reduce the number of dosage forms administered to the patient. For example, VX-950 can be formulated in one dosage form and any additional agents can be formulated together or in another dosage form. VX-950 can be administered, for example, before, after, or during the administration of the additional agent.

  The disclosed methods can also include administering a cytochrome P450 monooxygenase inhibitor. CYP inhibitors may be useful for increasing hepatic concentrations and / or increasing blood levels of compounds that are inhibited by CYP (eg, VX-950).

  The benefits of improved drug pharmacokinetics (eg, by administration of CYP inhibitors) are well recognized in the art. By administration of a CYP inhibitor, the present disclosure provides for reduced metabolism of the protease inhibitor, VX-950. Thereby, the pharmacokinetics of the protease inhibitor is improved. The benefits of improved drug pharmacokinetics are well recognized in the art. Such improvements can lead to increased blood levels of the protease inhibitor. More importantly for HCV therapy, this improvement can result in increased concentrations of the protease inhibitor in the liver.

  In the disclosed method, the amount of CYP inhibitor administered is to increase the blood level of VX-950 compared to the blood level of this protease inhibitor in the absence of the CYP inhibitor. It is a sufficient amount. Thus, advantageously, even lower doses of protease inhibitors can be used (as compared to administration of protease inhibitors alone) in the disclosed methods.

  Accordingly, another embodiment of the present disclosure provides a method of increasing blood concentration or increasing hepatic concentration of VX-950 in a patient receiving VX-950, the method comprising a therapeutically effective amount of VX -Administering a -950 and cytochrome P450 monooxygenase inhibitor to the patient.

  In addition to treating patients infected with hepatitis C, the methods of the present disclosure can be used to prevent a patient from becoming infected with hepatitis C. Accordingly, one embodiment of the present disclosure provides a method for preventing hepatitis C virus infection in a patient comprising: a) any form of VX-950 of the present disclosure, any solid dispersion The body or any composition; and b) administering a cytochrome P450 monooxygenase inhibitor to the patient.

  As will be appreciated by those skilled in the art, when the method of the present disclosure is used for prophylactic treatment of a patient, if the patient has been infected with hepatitis C virus, the method is used to treat the infection. Can do. Accordingly, one embodiment of the present disclosure provides VX-950 of any form of the present disclosure, any solid dispersion or composition, and a cytochrome P450 monooxygenase inhibitor, wherein the inhibitor Is present in a therapeutically effective amount for treating or preventing hepatitis C infection in a patient.

  Where an embodiment of the present disclosure includes a CYP inhibitor, any CYP inhibitor that improves the pharmacokinetics of VX-950 can be used in the methods of the present disclosure. These CYP inhibitors include ritonavir (International Application WO 94/14436), ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporine, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, Indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delaviridine, erythromycin, VX-944 and VX-497 are included, but are not limited thereto. Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporine and chromethiazole. For preferred dosage forms of ritonavir, see US Pat. No. 6,037,157 and references cited therein: US Pat. No. 5,484,801, US patent application Ser. No. 08 / 402,690, and international applications. See WO 95/07696 and WO 95/09614.

  The structure of VX-944 is given below:

ＶＸ−４９７は、ＩＭＰＤＨ阻害剤である。ＶＸ−４９７とＰＥＧ化ＩＦＮ−αとリバビリンの組み合わせは、ＨＣＶ治療のために、現在、臨床開発中である［Ｗ．Ｍａｒｋｌａｎｄら，Ａｎｔｉｍｉｃｒｏｂｉａｌ ＆ Ａｎｔｉｖｉｒａｌ Ｃｈｅｍｏｔｈｅｒａｐｙ．４４，ｐ．８５９（２０００）；米国特許第６，５４１，４９６号］。

VX-497 is an IMPDH inhibitor. A combination of VX-497, PEGylated IFN-α and ribavirin is currently in clinical development for the treatment of HCV [W. Markland et al., Antimicrobial & Antibiological Chemotherapy. 44, p. 859 (2000); US Pat. No. 6,541,496].

シトクロムＰ５０モノオキシゲナーゼ活性の能力を測定するための方法は、公知である（例えば、米国特許第６，０３７，１５７号、およびＹｕｎら，Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ＆ Ｄｉｓｐｏｓｉｔｉｏｎ，ｖｏｌ．２１，ｐｐ．４０３−４０７（１９９３）参照）。

Methods for measuring the ability of cytochrome P50 monooxygenase activity are known (eg, US Pat. No. 6,037,157, and Yun et al., Drug Metabolism & Disposition, vol. 21, pp. 403-407). 1993)).

  A CYP inhibitor utilized in the present disclosure may be an inhibitor of only one isozyme, or may be an inhibitor of more than one isozyme. If a CYP inhibitor inhibits more than one isozyme, the inhibitor can nevertheless selectively inhibit one isozyme over another. Any such CYP inhibitor can be used in the disclosed methods.

  In the methods of the present disclosure, the CYP inhibitor may be administered in the same or separate dosage forms together with any form of VX-950, any solid dispersion or any composition of the present disclosure. it can.

  When the CYP inhibitor and the other components of the concomitant drug are administered in separate dosage forms, each inhibitor can be administered at about the same time. Alternatively, the CYP inhibitor can be administered within any period near the administration of the concomitant drug. That is, the CYP inhibitor can be administered before, with, or after each component of the concomitant drug. The administration period should be such that the CYP inhibitor affects the metabolism of the components of the concomitant drug, preferably VX-950. For example, when VX-950 is administered first, the CYP inhibitor must be administered before VX-950 is substantially metabolized and / or excreted (eg, within the half-life of VX-950).

  In order that this disclosure be more fully understood, the following examples are set forth. These examples are for illustrative purposes only and should not be construed as limiting the scope of the disclosure in any way.

  VX-950 can generally be prepared by methods known to those skilled in the art (see, eg, International Application WO 02/18369). HCV inhibition can be tested by HCV assay according to known methods.

  For the solid dispersion formulations presented in Examples 1-6, VX-950 and various amounts of HPMCAS-HG (hypromellose acetate succinate, HG grade, Shin-Etsu Chemical Co., Ltd.) polymer, HPMC-60SH50 ( Metrose, Shin-Etsu Chemical Co., Ltd.) polymer and SLS (sodium lauryl sulfate, Sigma / Fisher) surfactant were used. Spray drying was performed, followed by post-drying with a certified vacuum dryer. Success criteria include production of batches in reasonable yields (> 60%), low residual solvent (<400 ppm for total OVI), and meeting target powder properties (mainly particle size and bulk / tap density) As well as meeting specifications for assay and purity.

  For Examples 1-6, a formulation was prepared using a 80/20 (weight / weight) mixture of methylene chloride and acetone at a total solids concentration of about 10% by weight.

(Example 1)
A solid dispersion was prepared containing the following ingredients:
Table 1: Formulation composition: 55 / 24.4 / 19.6 / 1 (weight / weight / weight / weight) VX-950 / HPMCAS-HG / HPMC-60SH / SLS per 1.250 kg VX-950 (22 727 kg total batch size; 2.273 kg total solids).

（実施例２）
次の成分を含む固体分散体を調製した：
表２：製剤組成：１．２５０ｋｇのＶＸ−９５０当たり５５／１４．７／２９．３／１（重量／重量／重量／重量）のＶＸ−９５０／ＨＰＭＣＡＳ−ＨＧ／ＨＰＭＣ−６０ＳＨ／ＳＬＳ（２２．７２７ｋｇの全バッチサイズ；２．２７３ｋｇの全固形分）。

(Example 2)
A solid dispersion was prepared containing the following ingredients:
Table 2: Formulation composition: 55 / 14.7 / 29.3 / 1 (weight / weight / weight / weight) VX-950 / HPMCAS-HG / HPMC-60SH / SLS per 1.250 kg VX-950 (22 727 kg total batch size; 2.273 kg total solids).

（実施例３）
次の成分を含む固体分散体を調製した：
表３：製剤組成：１．２５０ｋｇのＶＸ−９５０当たり６０／２４．４／１４．６／１（重量／重量／重量／重量）のＶＸ−９５０／ＨＰＭＣＡＳ−ＨＧ／ＨＰＭＣ−６０ＳＨ／ＳＬＳ（２０．８３ｋｇの全バッチサイズ；２．０８３ｋｇの全固形分）。

(Example 3)
A solid dispersion was prepared containing the following ingredients:
Table 3: Formulation composition: 60 / 24.4 / 14.6 / 1 (weight / weight / weight / weight) VX-950 / HPMCAS-HG / HPMC-60SH / SLS per 1.250 kg VX-950 (20 .83 kg total batch size; 2.083 kg total solids).

（実施例４）
次の成分を含む固体分散体を調製した：
表４：製剤組成：１．２５０ｋｇのＶＸ−９５０当たり６５／１７／１７／１（重量／重量／重量／重量）のＶＸ−９５０／ＨＰＭＣＡＳ−ＨＧ／ＨＰＭＣ−６０ＳＨ／ＳＬＳ（１９．２３ｋｇの全バッチサイズ；１．９２３ｋｇの全固形分）。

(Example 4)
A solid dispersion was prepared containing the following ingredients:
Table 4: Formulation composition: 65/17/17/1 (weight / weight / weight / weight) VX-950 / HPMCAS-HG / HPMC-60SH / SLS per 1.250 kg VX-950 (19.23 kg total Batch size; 1.923 kg total solids).

（実施例５）
次の成分を含む固体分散体を調製した：
表５：製剤組成：１．２５０ｋｇのＶＸ−９５０当たり７０／９．７／１９．３／１（重量／重量／重量／重量）のＶＸ−９５０／ＨＰＭＣＡＳ−ＨＧ／ＨＰＭＣ−６０ＳＨ／ＳＬＳ（１７．８６ｋｇの全バッチサイズ；１．７８６ｋｇの全固形分）。

(Example 5)
A solid dispersion was prepared containing the following ingredients:
Table 5: Formulation composition: 70 / 9.7 / 19.3 / 1 (weight / weight / weight / weight) VX-950 / HPMCAS-HG / HPMC-60SH / SLS per 1.250 kg VX-950 (17 .86 kg total batch size; 1.786 kg total solids).

（実施例６）
次の成分を含む固体分散体を調製した：
表６：製剤組成：１．２５０ｋｇのＶＸ−９５０当たり６０／３９／０／１（重量／重量／重量／重量）のＶＸ−９５０／ＨＰＭＣＡＳ−ＨＧ／ＨＰＭＣ−６０ＳＨ／ＳＬＳ（２０．８３３ｋｇの全バッチサイズ；２．０８３ｋｇの全固形分）。

(Example 6)
A solid dispersion was prepared containing the following ingredients:
Table 6: Formulation composition: 60/39/0/1 (weight / weight / weight / weight) VX-950 / HPMCAS-HG / HPMC-60SH / SLS (20.833 kg total) per 1.250 kg VX-950 Batch size; 2.083 kg total solids).

（実施例７）
製造プロセスの概要のフローチャートを図１に与える。

(Example 7)
A flow chart outlining the manufacturing process is given in FIG.

The process flow performed for the dispersions described in Examples 1-6 is as follows:
A) Preparation of solution and spray dryer 1) Methylene chloride was prepared in an equilibrium solvent tank.

    2) An appropriate amount of acetone was prepared in the solution reactor. The corrected scale confirmed the exact amount of solvent filled.

    3) The solution reactor was filled with SLS and solubilized. The corrected scale confirmed the exact amount of filled solid.

    4) An appropriate amount of methylene chloride was prepared in the solution reactor. The corrected scale confirmed the exact amount of solvent filled.

    5) The remaining solids (HPMCAS-HG, HPMC-60SH50, and VX-950) were charged to the solution reactor in the order listed, solubilizing one at a time. The solids were mixed up to 10% by weight with a mixture of methylene chloride (dichloromethane) and acetone (80/20 weight / weight). The resulting batch was inspected for appearance and viscosity once dissolved.

    6) A Niro 1.0 mm two-liquid nozzle was placed approximately 5 cm above the spray-drying vessel and examined for proper atomization with an equilibrium solvent.

B) Start of spray dryer 1) The spray dryer was almost discharged and heated to temperature. The operator confirmed that the collection pot was dried.

    2) Equilibrated solvent was sprayed until all parameters reached equilibrium and were constant.

    3) As soon as the spray dryer reached equilibrium, spray drying of the feed solution was started.

    4) The dry particles were inertially separated from the process gas by a cyclone and collected in a polyethylene bag. The process gas particulates were then filtered and concentrated to remove the process solvent.

    5) An initial sample was taken and examined for particle size distribution and bulk and tap density, and by GC for methylene chloride, acetone, ethyl acetate and toluene.

      a) If the particle size distribution and density were within acceptable criteria and were close to the target, the process was continued and samples were taken according to the sampling plan.

      b) If the particle size distribution and density are not within acceptable criteria and are not close to the target, the process is changed as necessary (to change one or more of the discharge temperature, feed rate or atomization rate). Optimized). When the sample was within specification, the process was started with the latest parameters.

C) Ongoing spray drying process 1) Samples were taken according to the sampling plan.

    2) Write down any changes to the machining parameters.

    3) The occurrence of any stoppages or deviations from continuous operation was noted.

    4) Upon completion of spray drying of the feed solution, the equilibration solvent was changed and the shutdown procedure continued.

D) Post-drying process 1) The spray-dried dispersion was filled in a certified vacuum drying phase. Samples were taken according to the sampling plan.

    2) Drying was then continued until all residual solvent (eg methylene chloride, acetone) was below the set specification.

E) Inspection, packaging, shipping 1) Samples of this dispersion were inspected for residual solvent (eg methylene chloride, acetone), particle size and distribution, bulk and tap density, assay / impurities, XRD and SEM.

Equipment A pilot scale reactor (R31) equipped with a stirrer and thermal circuit was used to mix the initial batch solution. A pilot scale spray dryer, SD81 (Niro mobile small spray dryer with expansion chamber) was used in normal spray drying mode. A Niro 1.0 mm two-part sprayer was used, which was placed approximately 5 cm above the spray drying vessel. An inertial cyclone separated the product from the process gas and solvent vapor. The filter bag then collected particulates that were not separated by the cyclone. The resulting gas was concentrated to remove the process solvent and vented (open cycle).

  FIG. 2 is a schematic diagram of the spray drying process.

  The resulting product was transferred to a certified vacuum dryer (EV10 or similar) for residual solvent drying.

Basic process controls and parameters Basic process controls and parameters were used for both spray drying and vacuum drying processes. Primary process control parameters were identified by preliminary survey batches.

The basic process controls and parameters for the spray drying process that had to be monitored and recorded over the entire operating time are:
● Installed two-component nozzle ● Atomization gas pressure and altitude of rotameter%
● Inlet temperature ● Cooler temperature set point (about -15 ℃)
Met.

The basic process metrics for the spray drying process that had to be monitored and recorded over the entire operating time are:
● Discharge temperature ● ΔP of drying gas
● Average solution supply for all operations.

  Table 7 is a definition of spray drying process parameters / metrics, settings / ranges, and target guidelines.

  Table 7: Spray drying variables, settings and targets

材料
使用したすべての賦形剤およびプロセス溶媒は、本明細書において示すようなヨーロッパ薬局方、日本薬局方またはＵＳＰ／ＮＦの最新モノグラフに準拠する。すべての賦形剤よびプロセス溶媒は、認可を受けた供給業者から購入した。製造者発行の分析証明書は、信用されるであろうし、すべての材料は、ＩＤ試験されるであろう。

Materials All excipients and process solvents used comply with the latest monographs of the European Pharmacopeia, Japanese Pharmacopeia or USP / NF as indicated herein. All excipients and process solvents were purchased from authorized suppliers. The manufacturer-issued analysis certificate will be trusted and all materials will be ID tested.

  Table 8: Materials

追加の考慮事項
９重量％から２５重量％にわたる固形分濃度の分散体を製造することができる。例えば１０重量％の分散体を噴霧乾燥させることができる。

Additional considerations Dispersions with solid concentrations ranging from 9% to 25% by weight can be produced. For example, 10% by weight of the dispersion can be spray dried.

  A dispersion having a solvent range of 70/30 (w / w) methylene chloride / acetone to 100% methylene chloride can be spray dried. For example, the dispersion can be spray dried from 80/20 (weight / weight) methylene chloride / acetone.

  Dispersions having polymer (s), eg, HPMCAS, and / or HPMCAS-HG / HPMC combinations can be spray dried. For example, a dispersion having a combination of HPMCAS-HG / MPMC-60SH50 can be spray dried.

  The dispersion can be spray dried with either a two liquid nozzle or a hydraulic nozzle. For example, the dispersion can be spray dried with a two-component nozzle.

Handling and Storage Standards Once the production is complete, package the dispersion.

(Example 8)
A solid dispersion of amorphous VX-950 containing the ingredients given in Table 9 below (as weight percent of the total dispersion) was prepared and the dissolution of the solid dispersion in fasting SGF at 37.5 ° C. was measured. . The dissolution graph is shown in FIG.

  Table 9: VX-950 solid dispersion

（実施例９）
下の表１０に（全分散体の重量パーセントとして）与える成分を含む非晶質ＶＸ−９５０の固体分散体を調製し、３７．５℃の空腹時ＳＧＦへの固体分散体の溶解を測定した。溶解グラフを図４に示す。
表１０：ＶＸ−９５０の固体分散体

Example 9
A solid dispersion of amorphous VX-950 containing the ingredients given in Table 10 below (as weight percent of the total dispersion) was prepared and the dissolution of the solid dispersion in fasting SGF at 37.5 ° C. was measured. . A dissolution graph is shown in FIG.
Table 10: VX-950 solid dispersion

（実施例１０）
下の表１１に（全分散体の重量パーセントとして）与える成分を含む非晶質ＶＸ−９５０の固体分散体を調製し、３７．５℃の空腹時ＳＧＦへの固体分散体の溶解を測定した。溶解グラフを図５に示す。

(Example 10)
A solid dispersion of amorphous VX-950 containing the ingredients given in Table 11 below (as weight percent of the total dispersion) was prepared and the dissolution of the solid dispersion in fasting SGF at 37.5 ° C. was measured. . The dissolution graph is shown in FIG.

  Table 11: VX-950 solid dispersion

（実施例１１）
表１２に示す溶媒混合物を用いて、非晶質ＶＸ−９５０の以下の固体分散体を調製した。それらの分散体についてのＤ５０およびバルク密度を決定した。含有率についての値は、重量パーセントで与える。

Example 11
The following solid dispersion of amorphous VX-950 was prepared using the solvent mixture shown in Table 12. The D50 and bulk density for those dispersions was determined. Values for content are given in weight percent.

（実施例１２）
本開示の非晶質ＶＸ−９５０の噴霧乾燥分散体は、錠剤の作製に使用することができる。この錠剤は、溶融粒状体に調合されたビタミンＥ ＴＰＧＳを含む、表１３に示す製剤を含有し得る：
表１３：ＶＸ−９５０の噴霧乾燥分散体を含有する錠剤化製剤

Example 12
The spray-dried dispersion of amorphous VX-950 of the present disclosure can be used to make tablets. The tablet may contain the formulation shown in Table 13 comprising vitamin E TPGS formulated into molten granules:
Table 13: Tableted formulations containing spray dried dispersion of VX-950

（実施例１３）
表１４における実施例は、調製することができる、非晶質ＶＸ−９５０を含有する噴霧乾燥分散体である：（重量パーセントを示す）
表１４：ＶＸ−９５０の固体分散体

(Example 13)
The example in Table 14 is a spray-dried dispersion containing amorphous VX-950 that can be prepared: (indicating weight percent)
Table 14: VX-950 solid dispersion

本開示の多数の実施形態を説明した。だがやはり、本開示の精神および範囲を逸脱することなく様々な変更を行うことができることは理解されるであろう。従って、他の実施形態は、後続のクレームの範囲内である。

A number of embodiments of the disclosure have been described. However, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other embodiments are within the scope of the following claims.

FIG. 1 illustrates a flow chart for the manufacturing process, control, sampling and inspection of a preparation of a spray-dried dispersion in which amorphous VX-950 is a component. FIG. 2 illustrates a schematic diagram of a spray-drying manufacturing process for a preparation of a spray-dried dispersion in which amorphous VX-950 is a component. FIG. 3 illustrates a line graph showing the dissolution rate of various VX-950 solid dispersions in fasting SGF at 37.5 ° C. FIG. 4 illustrates a line graph showing the dissolution rate of various VX-950 solid dispersions in fasting SGF at 37.5 ° C. FIG. 5 illustrates a line graph showing the dissolution rate of various VX-950 solid dispersions in fasting SGF at 37.5 ° C.

Claims (85)

  A solid dispersion comprising amorphous VX-950 and a number of polymers.   The solid dispersion of claim 1, comprising less than about 40% crystalline VX-950.   The solid dispersion of claim 1, which is substantially free of crystalline VX-950.   The solid dispersion of claim 1 further comprising a surfactant or an inert pharmaceutically acceptable substance.   The solid dispersion according to claim 4, wherein the surfactant is sodium lauryl sulfate (SLS) or vitamin E or a derivative thereof.   The solid dispersion according to claim 5, wherein the surfactant is SLS.   The solid dispersion according to claim 5, wherein the surfactant is vitamin E or a derivative thereof.   The solid dispersion of claim 5, wherein the surfactant is present in an amount between about 0.1% and about 10%.   The solid dispersion of claim 1, wherein the multiple polymers comprise two polymers.   The solid dispersion of claim 9, wherein the multiple polymers comprise a cellulose polymer.   The solid dispersion according to claim 10, wherein the cellulose polymer is hydroxypropylmethylcellulose (HPMC).   The solid dispersion according to claim 10, wherein the cellulose polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).   The solid dispersion of claim 9, wherein the multiple polymers comprise two cellulose polymers.   The solid dispersion of claim 13, wherein one of the two cellulose polymers is hydroxypropyl methylcellulose (HPMC).   14. A solid dispersion according to claim 13, wherein one of the two cellulose polymers is hydroxypropyl methylcellulose acetate succinate (HPMCAS).   The solid dispersion of claim 13, wherein the multiple polymers comprise HPMC and HPMCAS.   14. A solid dispersion according to claim 13, comprising a surfactant or an inert pharmaceutically acceptable substance.   The solid dispersion according to claim 17, wherein the surfactant is SLS or vitamin E or a derivative thereof.   The solid dispersion according to claim 18, wherein the surfactant is SLS.   The solid dispersion according to claim 18, wherein the surfactant is vitamin E or a derivative thereof.   21. The solid dispersion of claim 20, wherein the surfactant is present in an amount between about 0.1% and about 10%.   The first polymer is present in an amount between about 1% and about 99% and the second polymer is present in an amount between about 1% and about 99%, the first and second polymers The solid dispersion of claim 9, wherein the total amount is 100% of the total polymer present in the solid dispersion.   24. The solid dispersion of claim 22, wherein the first polymer is HPMCAS.   24. The solid dispersion of claim 22, wherein the second polymer is HPMC.   The first polymer of claim 9, wherein the first polymer is present in an amount between about 28% and about 38%, and the second polymer is present in an amount between about 62% and about 72%. Solid dispersion.   The first polymer of claim 9, wherein the first polymer is present in an amount between about 47% and about 57%, and the second polymer is present in an amount between about 43% and about 53%. Solid dispersion.   The first polymer of claim 9, wherein the first polymer is present in an amount between about 58% and about 68%, and the second polymer is present in an amount between about 32% and about 42%. Solid dispersion.   The first polymer of claim 9, wherein the first polymer is present in an amount between about 45% and about 55%, and the second polymer is present in an amount between about 45% and about 55%. Solid dispersion.   2. The multiple polymers of claim 1, wherein the multiple polymers reduce the amount or rate of crystallization of amorphous VX-950 by at least 10% compared to a solid dispersion that is not in the presence of the multiple polymers. Solid dispersion.   The solid dispersion of claim 1, wherein the multiple polymers improve the physical stability of amorphous VX-950 by at least 10% compared to a solid dispersion in the absence of the multiple polymers. body.   The plurality of polymers increase the chemical or physical stability of the solid dispersion when stored by at least 10% as compared to a solid dispersion not in the presence of the multiple polymers. The solid dispersion according to 1.   The solid dispersion of claim 1, wherein the VX-950 has improved physical or chemical stability relative to amorphous VX-950 that is not in the presence of the multiple polymers.   The solid dispersion of claim 1, wherein the multiple polymers are present in an amount of about 5 wt% to about 80 wt%.   2. The composition of claim 1, comprising about 55% VX-950, about 19.6% HPMC polymer, such as HPMC 60SH50, about 24.4% HPMCAS polymer, such as HPMCAS-HG, and about 1% surfactant. Solid dispersion.   Solid dispersion comprising about 55% VX-950, about 29.3% HPMC polymer, eg HPMC 60SH50, about 14.7% HPMCAS polymer, eg HPMCAS-HG, and about 1% surfactant, eg SLS The solid dispersion according to claim 1, comprising:   Claims comprising about 60% VX-950, about 14.6% HPMC polymer, such as HPMC 60SH50, about 24.4% HPMCAS polymer, such as HPMCAS-HG, and about 1% surfactant, such as SLS. The solid dispersion according to 1.   2. The composition of claim 1, comprising about 65% VX-950, about 17% HPMC polymer, e.g. HPMC60SH50, about 17% HPMCAS polymer, e.g. HPMCAS-HG, and about 1% surfactant, e.g. SLS. Solid dispersion.   Claims comprising about 70% VX-950, about 19.3% HPMC polymer, such as HPMC60SH50, about 9.7% HPMCAS polymer, such as HPMCAS-HG, and about 1% surfactant, such as SLS. The solid dispersion according to 1.   The solid dispersion of claim 1, wherein at least about 80% by weight of the VX-950 is in an amorphous form.   40. The solid dispersion of claim 39, wherein substantially all of the VX-950 is in an amorphous form.   The solid dispersion according to claim 1, wherein the VX-950 is a mixture of L-isomer and D-isomer.   The solid dispersion of claim 1, wherein the VX-950 is a substantially pure L-isomer.   Solid dispersion according to claim 1, obtained by spray drying.   A pharmaceutical composition comprising amorphous VX-950 and a number of polymers.   45. The composition of claim 44, wherein the amorphous VX-950 is substantially free of crystalline VX-950.   A pharmaceutical composition comprising amorphous VX-950 and a number of polymers as a solid dispersion and one or more of a surfactant, an inert pharmaceutically acceptable substance or a pharmaceutically acceptable carrier. object.   47. The pharmaceutical composition of claim 46, wherein the multiple polymers comprise one or more water soluble polymers or partially water soluble polymers.   47. The pharmaceutical composition of claim 46, wherein the VX-950 has improved physical or chemical stability compared to crystalline VX-950.   49. The multiple polymers of claim 46, wherein the multiple polymers reduce the amount or rate of crystallization of amorphous VX-950 by at least 10% as compared to a pharmaceutical composition in the absence of the multiple polymers. Pharmaceutical composition.   47. The medicament of claim 46, wherein the multiple polymers increase the chemical or physical stability of the pharmaceutical composition by at least 10% compared to a pharmaceutical composition in the absence of the multiple polymers. Composition.   47. The pharmaceutical composition of claim 46, wherein said VX-950 has improved physical or chemical stability compared to amorphous VX-950 that is not in the presence of said multiple polymers.   47. The pharmaceutical composition of claim 46, wherein the multiple polymers comprise HPMC.   47. The pharmaceutical composition of claim 46, wherein the multiple polymers comprise HPMCAS. An amorphous solid dispersion of VX-950, wherein said VX-950 comprises about 25-85% (w / w) of the pharmaceutical composition;
A number of polymers (in which case the number comprises two cellulose polymers, and the number of polymers comprises about 15-75% (weight / weight) of the pharmaceutical composition), and a surfactant ( In this case, the surfactant constitutes about 0.5-2% (weight / weight) of the pharmaceutical composition)
A pharmaceutical composition comprising   55. The pharmaceutical composition according to claim 54, wherein the cellulose polymer is HPMC.   55. The pharmaceutical composition according to claim 54, wherein the cellulose polymer is HPMCAS.   55. The pharmaceutical composition according to claim 54, wherein the surfactant is sodium lauryl sulfate or vitamin E TPGS. Said VX-950 comprises from about 55% to about 70% (w / w) of the pharmaceutical composition;
The surfactant is sodium lauryl sulfate or vitamin E TPGS, and constitutes about 1% (weight / weight) of the pharmaceutical composition, and the multiple polymers comprise HPMC and HPMCAS; About 44% to about 29% (w / w) of the product, resulting in a total of 100% (w / w) of the composition;
55. A pharmaceutical composition according to claim 54. Said VX-950 comprises about 55% (w / w) of the pharmaceutical composition;
The multiple polymers comprise about 44% (w / w) of the pharmaceutical composition, and the surfactant is sodium lauryl sulfate or vitamin E TPGS, and about 1% of the pharmaceutical composition ( (Weight / weight)
55. A pharmaceutical composition according to claim 54.   60. The pharmaceutical composition of claim 59, wherein the multiple polymers comprise about 55.5% (w / w) HPMCAS and about 44.5% (w / w) HPMC. Said VX-950 comprises about 55% (w / w) of the pharmaceutical composition;
The multiple polymers comprise about 44% (w / w) of the pharmaceutical composition, and the surfactant is sodium lauryl sulfate or vitamin E TPGS, and about 1% of the pharmaceutical composition ( (Weight / weight)
55. A pharmaceutical composition according to claim 54.   62. The pharmaceutical composition of claim 61, wherein the multiple polymers comprise about 33% (w / w) HPMCAS and about 67% (w / w) HPMC. Said VX-950 comprises about 60% (w / w) of the pharmaceutical composition;
The multiple polymers comprise about 39% (w / w) of the pharmaceutical composition, and the surfactant is sodium lauryl sulfate or vitamin E TPGS, and about 1% of the pharmaceutical composition ( (Weight / weight)
55. A pharmaceutical composition according to claim 54.   64. The pharmaceutical composition of claim 63, wherein the multiple polymers comprise about 63% (w / w) HPMCAS and about 36% (w / w) HPMC. Said VX-950 comprises about 65% (w / w) of the pharmaceutical composition;
The multiple polymers comprise about 34% (w / w) of the pharmaceutical composition, and the surfactant is sodium lauryl sulfate or vitamin E TPGS, and about 1% of the pharmaceutical composition ( (Weight / weight)
55. A pharmaceutical composition according to claim 54.   66. The pharmaceutical composition of claim 65, wherein the multiple polymers comprise about 50% (w / w) HPMCAS and about 50% (w / w) HPMC. Said VX-950 comprises about 70% (w / w) of the pharmaceutical composition;
The multiple polymers comprise about 29% (w / w) of the pharmaceutical composition, and the surfactant is sodium lauryl sulfate or vitamin E TPGS, and about 1% of the pharmaceutical composition ( (Weight / weight)
55. A pharmaceutical composition according to claim 54.   68. The pharmaceutical composition of claim 67, wherein the multiple polymers comprise about 33% (w / w) HPMCAS and about 67% (w / w) HPMC.   A process for preparing a solid dispersion comprising amorphous form of VX-950 and multiple polymers comprising spray drying VX-950 and multiple polymers to produce a solid dispersion of VX-950 .   70. The method of claim 69, comprising combining the VX-950, the multiple polymers, and a suitable solvent to form a mixture, and then spray drying the mixture to obtain a solid dispersion of VX-950. 70. The method of claim 69, comprising: a) making a mixture comprising VX-950 and said multiple polymers and solvent; and b) spray-drying the mixture to produce a solid dispersion comprising VX-950. the method of.   72. The method of claim 71, wherein the multiple polymers comprise HPMC or HPMCAS.   72. The method of claim 71, wherein the multiple polymers comprise HPMC and HPMCAS.   72. The method of claim 71, wherein the multiple polymers are present in the solid dispersion in an amount from about 20% to about 60% by weight.   70. The method of claim 69, wherein the mixture further comprises a surfactant.   76. The method of claim 75, wherein the surfactant is sodium lauryl sulfate (SLS) or vitamin E TPGS.   72. The method of claim 71, wherein the solvent comprises methylene chloride.   72. The method of claim 71, wherein the solvent comprises acetone.   72. The method of claim 71, wherein the solvent comprises about 0% to about 30% acetone and about 70% to about 100% methylene chloride.   72. The method of claim 71, wherein the solvent comprises about 0% to about 40% acetone and about 60% to about 100% methylene chloride.   72. A solid dispersion prepared according to the method of claim 71.   A method of treating HCV infection in a mammal comprising administration of the solid dispersion of claim 1.   Immunomodulators; antiviral drugs; other inhibitors of HCV NS3 / 4A protease; other inhibitors of IMPDH; inhibitors of targets other than NS3 / 4A protease in the HCV life cycle; ribosome internal entry inhibitors, broad spectrum viruses 83. The method of claim 82 comprising administration of an additional agent selected from an inhibitor; a cytochrome P-450 inhibitor; or a combination thereof.   A pharmaceutical pack or kit comprising a solid dispersion of VX-950 according to claim 1.   An oral formulation comprising a solid dispersion of VX-950 according to claim 1.

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